How should worsening in osteoarthritis be defined? Development and initial validation of preliminary criteria for clinical worsening in knee and hip osteoarthritis

OBJECTIVES: There is a need to define and validate measures of clinical worsening in knee and hip osteoarthritis (OA). The objectives of this exploratory project were: (i) to characterize worsening criteria in knee and hip OA using psychometric methods; (ii) to estimate their sensitivity and specificity; and (iii) to validate and compare these criteria with worsening criteria previously described in the literature. METHOD: An Expert Group reached consensus on 10 sets of worsening criteria to be tested in observational data sets of patients with knee or hip OA who received multimodal conservative treatment. These sets included 219 patients (derivation cohort) and 296 patients (validation cohort). We estimated minimal clinically important worsening (MCIW) values for pain, function, stiffness, and patient global assessment, and tested candidate worsening criteria in the derivation cohort. Finally, using patient judgement, we examined the sensitivity and specificity of literature-based as well as candidate worsening criteria in the validation cohort. RESULTS: Literature-based worsening criteria were found to have high specificity (range 60-92%) but low sensitivity (range 22-59%). Two out of 10 candidate worsening criteria constructed by the Expert Group showed an acceptable combination of sensitivity and specificity in the derivation cohort, which was confirmed in the validation cohort (ranging from 54% to 65% and 67% to 74%, respectively). CONCLUSIONS: This is the first study to describe symptomatic worsening criteria based on expert consensus after examining the performance of candidate criteria derived from the literature applied to data in an observational study. The newly proposed worsening criteria show an acceptable combination of sensitivity and specificity

Young scholar presentation: A review of medium chain fatty acids and their recent role in feed safety.

Medium chain fatty acids (MCFA), have been researched extensively to reduce the likelihood of animal feed being contaminated by biological pathogens, including bacteria and viruses. Medium chain fatty acids have shown to be bactericidal and bacteriostatic by incorporating themselves into the lipid membrane of bacteria, which alters the cell membrane permeability leading to cell death. However, the effectiveness can be dependent upon the MCFA chain length and species of bacteria. Most research completed prior to 2013 focused on the antimicrobial properties of MCFA. However, with the emergence of Porcine Epidemic Diarrhea Virus (PEDV), MCFA began to gain more attention for their potential uses in feed safety and swine nutrition as a potential antiviral additive. Medium chain fatty acids have shown repeated success against PEDV in vivo and in vitro. Notably, 2% MCFA [1:1:1 blend of caproic, caprylic, and capric] was equally successful at mitigating PEDV as commercially-available formaldehyde products in complete swine feed (P>0.05). However, the effectiveness varies within feed matrix, as MCFA was not as effective as formaldehyde at mitigation in spray dried animal plasma and meat and bone meal (P<0.05). A lower concentration of the MCFA blend (1%), as well as the individual addition of 0.66% caproic, 0.66% caprylic, or 0.66% capric acids also enhanced the RNA degradation of PEDV in complete swine feed (P<0.05). Other research has evaluated the same 2% MCFA blend in a transboundary based study, replicating the time and environmental condition that feed ingredients undertake during a trip from China to the United States. Again, the MCFA treated ingredients were deemed to be negative throughout the simulated transboundary trip (P<0.05). Medium chain fatty acids have also been evaluated as a surface decontaminate and as a potential feed mill flush step. However, the overall effectiveness was not as substantial as the results observed in the feed ingredient studies. Currently, it is not known what the exact mode of action of the MCFA is against PEDV, but it is hypothesize that the MCFA are interacting with the lipid bilayer envelope of the virus and altering the envelope in a way in which it cannot bind with the host receptors. This mode of action would be similar to that of the bacteria as both outer membranes consist of a lipid bilayer. Future research is now focused on the use of MCFA against other enveloped and non-enveloped swine viruses as well as an antibiotic alternative in swine production

Effects of chlortetracycline alone or in combination with direct fed microbials on nursery pig growth performance and antimicrobial resistance of fecal Escherichia coli1

A total of 300 nursery pigs (initially 5.9 ± 0.05 kg BW) were used in a 42-d growth trial to evaluate the effects of feeding a therapeutic level of chlortetracycline (CTC) with or without direct fed microbials (DFM) on growth performance and antimicrobial resistance (AMR) of fecal Escherichia coli. CTC is a broad-spectrum in-feed antibiotic commonly used in the swine industry. Weaned pigs (~21 d of age) were allotted to pens based on initial BW and fed a common starter diet for 4 d. Pens were then blocked by BW and allotted to dietary treatments in a completely randomized block design. Dietary treatments were arranged in a 2 × 3 factorial consisting of combinations of CTC (none vs. 400 mg/kg from days 0 to 42) and DFM (0 vs. 0.05% DFM 1 vs. 0.05% DFM 2). Fecal samples were collected from three randomly selected pigs from each pen on days 0, 21, and 42 for E. coli isolation and AMR determination. Overall, pigs fed diets containing CTC had improved (P < 0.001) ADG, ADFI, and BW compared to those not fed CTC with no evidence for any effect of either DFM 1 or DFM 2. Regardless of CTC, inclusion of DFM 2 in diets improved (P < 0.05) ADFI from days 0 to 14 and on day 14 BW compared to diets that did not include DFM 2. The addition of CTC with or without DFMs to nursery pig diets increased (P < 0.05) the probability of AMR to tetracycline and ceftiofur of fecal E. coli isolates, but this resistance generally decreased (P < 0.05) over time. A decrease (P < 0.05) in AMR to ampicillin and tetracycline (TET) throughout the trial was observed, while resistance to ceftriaxone decreased (P < 0.020) from days 0 to 21 and increased from days 21 to 42 amongst dietary treatments regardless of CTC or DFM inclusion in the diet. A CTC × DFM × day interaction (P < 0.015) was observed for streptomycin, whereby from days 21 to 42 AMR increased in diets containing either CTC or DFM 1 alone, but the combination decreased resistance. There was no evidence for any effect of DFMs on AMR of fecal E. coli isolates to any other antibiotics evaluated. In conclusion, therapeutic levels of added CTC with or without DFM inclusion improved nursery pig performance, but increased AMR of fecal E. coli isolates to TET and ceftiofur. A moderate improvement in intake and day 14 BW was observed when DFM 2 was included in the diet with or without CTC, but, except for streptomycin, there was no evidence that added dietary DFMs affected resistance of fecal E. coli to antibiotics

Defining the minimum inhibitory concentration of synthetic and commercial medium chain fatty acid based products against salmonella typhimurium

Research has confirmed that a 2% inclusion rate of a blend of C6:0, C8:0, and C10:0 in swine diets and ingredients can reduce Salmonella enterica serotype Typhimurium. However, it is unclear how the chain length and concentration of medium chain fatty acids (MCFA) impacts bacteriostatic properties. This can be tested through a minimum inhibitory concentration (MIC) benchtop assay, which identifies the lowest concentration of a chemical that prevents visible growth of a bacterium. The objective of this set of experiments was to utilize MIC as a mechanism to screen commercial or developmental feed additives containing MCFA for potential to mitigate Salmonella Typhimurium. First, the MIC of four synthetic MCFA treatments (C6:0, C8:0, C10:0, and 1:1:1 ratio of C:6:C8:C10 blend) was determined for Salmonella Typhimurium. The MIC of each treatment was conducted in a modified microbroth dilution and had three replicates. The MIC of C6:0 and C8:0 (0.4 and 0.5%, respectively) were similar (P > 0.05) to one another, but lower (P 1.0%, respectively). It was therefore hypothesized that products containing high concentrations of C6:0 or C8:0 would have the greatest potential to mitigate Salmonella Typhimurium. Next, the fatty acid profile of 24 feed additive products that were commercially developed or in the development process and containing MCFA was determined via gas chromatography. As a result, four products in the development phase from varying companies plus coconut oil were selected as having a high potential for mitigating Salmonella Typhimurium based on their C6:0 and C8:0 levels. Development products 1, 2, 3, 4, and coconut oil contained 29.5, 43.1, 27.4, 0.98, and 6.82 mg/g of C6:0 and 123.20, 610.3, 248.7, 227.1, and 72.0 mg/g of C8:0, respectively. The MIC of these products vs. Salmonella Typhimurium was then determined. The MIC of Product 1 and Product 2 (0.5% and 1.3%, respectively) were similar (P > 0.05) to one another, but lower (P 5.0%). In summary, current or future feed additives containing high concentrations of C6:0 and C8:0 appear to be more effective at mitigating Salmonella Typhimurium than those containing C10:0. Furthermore, it is hypothesized that free MCFA have greater antibacterial potential than those in triglyceride form

Determination of the minimum inhibitory concentration of various medium chain fatty acid-based products in E. coli, Enterotoxigenic E. coli, and Campylobacter coli.

Research has demonstrated medium chain fatty acids (MCFA) are bactericidal and potential antibiotic alternatives. However, it is unknown how the type or level of MCFA impact bacteria growth. This can be tested through a minimum inhibitory concentration (MIC) benchtop assay, which identifies the lowest concentration of a chemical that prevents visible growth of a bacterium. Our objective was to determine the MIC of pure MCFA (Experiment 1) and products containing MCFA (Experiment 2) against generic E. coli, enterotoxigenic E. coli (ETEC), or Campylobacter coli (campy). Experiment 1 used a 4 × 3 factorial with four types of pure MCFA (C6:0, C8:0, C10:0, or 1:1:1 blend of C6:C8:C10) against the three bacteria and was repeated 3 times. All interactions and main effects were significant (P0.05) MIC against campy. This demonstrated that MCFA efficacy varies with MCFA type and bacteria. Pure MCFA are expensive and not easily available to producers. Thus, 24 commercially-available and developmental products were analyzed for MCFA concentration, with 5 selected based on their C6:0, C8:0, and C10:0 concentrations. In Experiment 2, these products were used in a 5 × 3 factorial to determine their MIC using the same procedures in Experiment 1. There were 5 MCFA products (4 developmental products + coconut oil) tested against three bacteria (E. coli, ETEC, and campy). Only the main effect of treatment was significant, resulting in products 1 and 2 having a lower (P<0.05) MIC than products 3, 4, and coconut oil. In summary, pure MCFA were bactericidal to E. coli, ETEC, and campy. However, their efficacy varied between bacteria. The efficacy of potential commercial products can be predicted based on their MCFA concentration, with the shorter chain MCFA having greater efficacy in the tested bacteria

Multiple Scan Chains for Power Minimization during Test Application in Sequential Circuits

This paper presents a new technique for power minimization during test application in sequential circuits using multiple scan chains. The technique is based on a new design for test architecture and a novel test application strategy which reduces spurious transitions in the circuit under test. To facilitate the reduction of spurious transitions, the proposed design for test architecture is based on classifying scan latches into compatible, incompatible and independent scan latches. Based on their classification, the scan latches are partitioned into multiple scan chains and a single extra test vector associated with each scan chain is computed. A new test application strategy which applies the extra test vector to primary inputs while shifting out test responses for each scan chain, minimizes power dissipation by eliminating the spurious transitions which occur in the combinational part of the circuit. The newly introduced multiple scan chain-based technique does not introduce performance degradation and minimizes clock tree power dissipation with minimal impact on both test area and test data overhead. Unlike previous approaches which are test set dependent and, hence, are not able to handle large circuits due to the complexity of the design space, this paper shows that with low test area and test data overhead substantial savings in power dissipation during test application are achieved in very low computational time for both small and large test sets. For example, in the case of the benchmark circuit s15850 it takes &lt;600s in computational time and &lt;1 percent in test area and test data overhead to achieve over 80 percent savings in power dissipation

Content and Construct Validity, Reliability, and Responsiveness of the Rheumatoid Arthritis Flare Questionnaire: OMERACT 2016 Workshop Report

Item does not contain fulltextOBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop a reliable way to identify and measure RA flares in randomized controlled trials (RCT). Here, we summarized the development and field testing of the RA Flare Questionnaire (RA-FQ), and the voting results at OMERACT 2016. METHODS: Classic and modern psychometric methods were used to assess reliability, validity, sensitivity, factor structure, scoring, and thresholds. Interviews with patients and clinicians also assessed content validity, utility, and meaningfulness of RA-FQ scores. RESULTS: People with RA in observational trials in Canada (n = 896) and France (n = 138), and an RCT in the Netherlands (n = 178) completed 5 items (11-point numerical rating scale) representing RA Flare core domains. There was moderate to high evidence of reliability, content and construct validity, and responsiveness. Factor analysis supported unidimensionality. Rasch analysis showed acceptable fit to the Rasch model, with items and people covering a broad measurement continuum and evidence of appropriate targeting of items to people, ordered thresholds, minimal differential item functioning by language, sex, or age. A summative score across items is defensible, yielding an interval score (0-50) where higher scores reflect worsening flare. The RA-FQ received endorsement from 88% of attendees that it passed the OMERACT Filter 2.0 "Eyeball Test" for instrument selection. CONCLUSION: The RA-FQ has been developed to identify and measure RA flares. Its review through OMERACT Filter 2.0 shows evidence of reliability, content and construct validity, and responsiveness. These properties merit its further validation as an outcome for clinical trials