Association of quantitative measures of medial meniscal extrusion with structural and symptomatic knee osteoarthritis progression - Data from the OAI FNIH biomarker study.

OBJECTIVE: To study the association of quantitative medial meniscal position measures with radiographic and symptomatic knee osteoarthritis (OA) progression over 2-4 years. METHODS: The FNIH OAI Biomarkers study comprised 600 participants in four subgroups: 194 case knees with combined structural (medial minimum joint space width (minJSW) loss ≥0.7 mm) and symptomatic (persistent Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale increase ≥9 [0-100 scale]) progression; 200 knees with neither structural nor symptomatic progression; 103 knees with isolated structural and 103 with isolated symptomatic progression. Coronal double echo at steady state (DESS) MRIs were used for segmenting five central slices of the medial meniscus. Associations with progression were examined using logistic regression (adjusted for demographic and clinical data). RESULTS: Greater baseline medial meniscal extrusion was associated with combined structural/symptomatic progression (OR 1.59; 95%CI: [1.25,2.04]). No relationship was observed for tibial plateau coverage or meniscal overlap distance. The two-year increase in meniscal extrusion (OR 1.48 [1.21, 1.83]), and reduction in tibial plateau coverage (OR 0.70 [0.58,0.86]) and overlap distance (OR 0.73 [0.60,0.89]) were associated with combined progression. Greater baseline extrusion was associated with isolated structural and less extrusion with isolated symptomatic progression. The longitudinal increase in meniscal extrusion, and reduction in tibial plateau coverage and overlap distance were associated with structural, but not with symptomatic progression. CONCLUSION: Baseline measures of medial meniscal extrusion were consistently positively associated with combined radiographic/symptomatic progression and with isolated structural, but not with isolated symptomatic progression. These measures may therefore allow one to assess the risk of structural knee OA progression and to monitor interventions restoring meniscal position and function.

Holistic Digitalization of the Nursing Internship Process in the Federal State of Salzburg with Strong User Involvement.

BACKGROUND: In the federal state of Salzburg, the harmonization of nursing internship took place from 2014-2019 as a joint effort of educational and internship providers. Currently the handling of these mostly paper pencil-based documents involves a manual process through different institutions and people. OBJECTIVES: The project provides the basis for the implementation of the "internship platform". In the future, this is to be the digital, state-of-the-art one-stop shop for the state-wide practical nursing training (in the form of immanent internships) at all training levels. METHODS: The process is influenced by modern requirements engineering techniques: As-is analysis of the internship process and related documents, contextual inquires in different internship providers, iterative focus group discussions focusing first on user stories, then on interface designs, and final user testing. RESULTS: Standardized workflow and authorization concept for all user groups, mandatory requirements for the software system, tested user interfaces, tender documents for EU-wide tender procedure. CONCLUSION: Positive feedback from all involved user groups on project goal, results and involvement in the process.

DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously.

We report the development of a platform of dual targeting Fab (DutaFab) molecules, which comprise two spatially separated and independent binding sites within the human antibody CDR loops: the so-called H-side paratope encompassing HCDR1, HCDR3 and LCDR2, and the L-side paratope encompassing LCDR1, LCDR3 and HCDR2. Both paratopes can be independently selected and combined into the desired bispecific DutaFabs in a modular manner. X-ray crystal structures illustrate that DutaFabs are able to bind two target molecules simultaneously at the same Fv region comprising a VH-VL heterodimer. In the present study, this platform is applied to generate DutaFabs specific for VEGFA and PDGF-BB, which show high affinities, physico-chemical stability and solubility, as well as superior efficacy over anti-VEGF monotherapy in vivo. These molecules exemplify the usefulness of DutaFabs as a distinct class of antibody therapeutics, which is currently being evaluated in patients.

Changes in Medial Meniscal Three-Dimensional Position and Morphology As Predictors of Knee Replacement in Rapidly Progressing Knee Osteoarthritis: Data From the Osteoarthritis Initiative.

OBJECTIVE: To assess whether quantitative changes in the meniscus predict progression from early knee osteoarthritis (OA) to knee replacement (KR). METHODS: A nested case-control study was conducted among Osteoarthritis Initiative participants: all 35 case knees with baseline Kellgren/Lawrence (K/L) grade ≤2 that had KR between 36 and 60 months were matched 1:1 by age, sex, and baseline K/L grade to 35 control knees without subsequent KR. Quantitative 3-dimensional medial meniscus position and morphologic measures were determined from magnetic resonance imaging at the visit just before KR and 2 years before. Paired t-tests and case-control odds ratios (ORs, standardized per SD of change in controls) were used to compare changes between groups. RESULTS: Cases (52% women, age 65 ± 7 years, body mass index [BMI] 30 ± 4 kg/m2 , K/L grades 0/1/2: 5/8/22 participants, respectively) and controls (52% women, age 64 ± 7 years, BMI 30 ± 5 kg/m2 , K/L grades 0/1/2: 9/4/22 participants, respectively) were similar. Compared to control knees, KR case knees displayed longitudinal changes, specifically, a decrease in tibial plateau coverage, an increase in meniscal extrusion, and a decrease in meniscal width. The odds for KR increased with greater reduction in the percentage of tibial plateau coverage (OR 2.28 [95% CI confidence interval (95% CI) 1.43, 3.64]), a greater increase in maximal extrusion (OR 1.40 [95% CI 1.12, 1.75]), and a greater reduction of mean meniscal width (OR 2.01 [95% CI 1.23, 3.26]). The odds for KR increased with medial compartment cartilage thickness loss (OR 2.86 [95% CI 1.51, 5.41]) for comparison. CONCLUSION: Quantitative measures of meniscal position and morphology are associated with subsequent KR in knees with rapidly progressing knee OA. These findings show that structural changes of the meniscus are related to an important clinical and economic outcome of knee OA.

Sensitivity to change and association of three-dimensional meniscal measures with radiographic joint space width loss in rapid clinical progression of knee osteoarthritis.

OBJECTIVE: To determine whether 3D meniscal measures had similar sensitivity to longitudinal change as cartilage thickness; to what extent these measures are associated with longitudinal joint space width (JSW) change; and whether the latter associations differ between minimum (mJSW) and fixed-location JSW. METHODS: Two-year changes in medial meniscal position and morphology, cartilage thickness (MRI) and minimum and fixed-location JSW (radiography) were determined in 35 Osteoarthritis Initiative knees [12 men, age: 67 (51-77) years; 23 women, age: 65 (54-78) years], progressing from baseline Kellgren-Lawrence grade ≤2 to knee replacement within 3-5 years. Multiple linear regression assessed the features contributing to JSW change. RESULTS: Meniscal measures, cartilage thickness and JSW displayed similar sensitivity to change (standardised response mean≤|0.76|). Meniscal changes were strongly associated with JSW change (r≤|0.66|), adding ≤20% to its variance in addition to cartilage thickness change. Fixed-location JSW change (multiple r2=72%) was more strongly related to cartilage and meniscal change than mJSW (61%). Meniscal morphology explained more of fixed-location JSW and meniscal position more of mJSW. CONCLUSION: Meniscal measures provide independent information in explaining the variance of radiographic JSW change. Fixed-location JSW appears to be more reflective of structural change than mJSW and, hence, a potentially superior measure of structural progression. KEY POINTS: • 3D positional/morphological meniscal measures change in rapidly progressing knees. • Similar sensitivity to 2-year change of quantitative meniscal/cartilage measures in rapid progression. • Changes in meniscal measures are strongly associated with radiographic JSW change. • Meniscal change provides information to explain JSW variance independent of cartilage. • Fixed-location JSW reflects structural disease stage more closely than minimum JSW.

The contribution of 3D quantitative meniscal and cartilage measures to variation in normal radiographic joint space width-Data from the Osteoarthritis Initiative healthy reference cohort.

OBJECTIVE: To explore to what extent three-dimensional measures of the meniscus and femorotibial cartilage explain the variation in medial and lateral femorotibial radiographic joint space width (JSW), in healthy men and women. METHODS: The right knees of 87 Osteoarthritis Initiative healthy reference participants (no symptoms, radiographic signs or risk factors of osteoarthritis; 37 men, 50 women; age 55.0±7.6; BMI 24.4±3.1) were assessed. Quantitative measures of subregional femorotibial cartilage thickness and meniscal position and morphology were computed from segmented magnetic resonance images. Minimal and medial/lateral fixed-location JSW were determined from fixed-flexion radiographs. Correlation and regression analyses were used to explore the contribution of demographic, cartilage and meniscal parameters to JSW in healthy subjects. RESULTS: The correlation with (medial) minimal JSW was somewhat stronger for cartilage thickness (0.54≤r≤0.67) than for meniscal (-0.31≤r≤0.50) or demographic measures (-0.15≤r≤0.48), in particular in men. In women, in contrast, the strength of the correlations of cartilage thickness and meniscal measures with minimal JSW were in the same range. Fixed-location JSW measures showed stronger correlations with cartilage thickness (r≥0.68 medially; r≥0.59 laterally) than with meniscal measures (r≤|0.32| medially; r≤|0.32| laterally). Stepwise regression models revealed that meniscal measures added significant independent information to the total variance explained in minimal JSW (adjusted multiple r2=58%) but not in medial or lateral fixed-location JSW (r2=60/51%, respectively). CONCLUSIONS: In healthy subjects, minimal JSW was observed to reflect a combination of cartilage and meniscal measures, particularly in women. Fixed-location JSW, in contrast, was found to be dominated by variance in cartilage thickness in both men and women, with somewhat higher correlations between cartilage and JSW in the medial than lateral femorotibial compartment. The significant contribution of the meniscus' position on minimal JSW reinforces concerns over validity of JSW as an indirect measure of hyaline cartilage.

Predictive Capacity of Thigh Muscle Strength in Symptomatic and/or Radiographic Knee Osteoarthritis Progression: Data from the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium.

Thigh muscle weakness is a risk factor for incident radiographic and symptomatic knee osteoarthritis (KOA). The role of thigh muscle weakness in radiographic and/or symptomatic KOA progression remains elusive. Five hundred twenty-seven knees of 527 Osteoarthritis Initiative participants with baseline Kellgren-Lawrence grades 1 to 3 were included in this nested case-control study evaluating whether baseline muscle strength predicted symptomatic and/or radiographic KOA progression. Case knees (n = 173) displayed both medial tibiofemoral joint space loss (≥0.7 mm) and a persistent increase in Western Ontario McMasters Osteoarthritis Index pain (≥9 on a 0- to 100-point scale) over 24 to 48 months from baseline. Control knees (n = 354) included 174 with neither radiographic nor symptomatic progression, 91 with radiographic progression only, and 89 with symptomatic progression only. Isometric knee extensor and flexor strength were recorded at baseline. Using logistic regression models, muscle strength was not associated with case status. However, knee extensor (odds ratio, 1.7; 95% confidence interval, 1.1-3.3; P = 0.035) and flexor weakness (odds ratio, 2.0; 95% confidence interval, 1.1, 3.3; P = 0.016) predicted isolated symptomatic progression in males, but not in females. The results indicate that thigh muscle strength may affect symptomatic and structural progression differently in males with KOA and identify an important window for potentially lowering risk of symptomatic osteoarthritis progression in men.