Drug Supply Chain Optimization for Adaptive Clinical Trials

With increasing interest in adaptive clinical trial designs, challenges are present to drug supply chain management which may offset the benefit of adaptive designs. Thus, it is necessary to develop an optimization tool to facilitate the decision making and analysis of drug supply chain planning. The challenges include the uncertainty of maximum drug supply needed, the shifting of supply requirement, and rapid availability of new supply at decision points. In this paper, statistical simulations are designed to optimize the pre-study medication supply strategy and monitor ongoing drug supply using real-time data collected with the progress of study. Particle swarm algorithm is applied when performing optimization, where feature extraction is implemented to reduce dimensionality and save computational cost

Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker - longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative

Abstract Introduction Bone marrow lesion (BML) size may be an important imaging biomarker for osteoarthritis-related clinical trials and reducing BML size may be an important therapeutic goal. However, data on the interrelationships between BML size, pain, and structural progression are inconsistent and rarely examined in the same cohort. Therefore, we evaluated the cross-sectional and longitudinal associations of BML volume with knee pain and joint space narrowing (JSN). Methods A BML volume assessment was performed on magnetic resonance images of the knee collected at the 24- and 48-month Osteoarthritis Initiative visits from a convenience sample of 404 participants in the progression cohort. During the same visits, knee pain was assessed with WOMAC pain scores and knee radiographs were acquired and scored for JSN. BML volume was summed to generate a total knee volume and an index tibiofemoral compartment volume (compartment with greater baseline JSN). Primary analyses included multiple linear regressions (outcome = pain, predictor = total knee BML volume) and logistic regressions (outcome = JSN, predictor = index tibiofemoral compartment BML volume). Results This sample was 49% female with a mean age of 63 (9.2 standard deviation (SD)) years, and 71% had radiographic osteoarthritis in the study knee. Larger baseline BMLs were associated with greater baseline knee pain (P = 0.01), the presence of JSN at baseline (odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.23 to 1.83), and JSN progression (OR = 1.27, 95%CI = 1.11 to 1.46). Changes in total knee BML volume had a positive association with changes in knee pain severity (P = 0.004) and this association may be driven by knees that were progressing from no or small baseline BMLs to larger BMLs. In contrast, we found no linear positive relationship between BML volume change and JSN progression. Instead, regression of medial tibiofemoral BML volume was associated with JSN progression compared to knees with no or minimal changes in BML volume (OR = 3.36, 95%CI = 1.55 to 7.28). However, follow-up analyses indicated that the association between JSN progression and BML volume change may primarily be influenced by baseline BML volume. Conclusion Large baseline BMLs are associated with greater baseline knee pain, the presence of JSN at baseline, and disease progression. Additionally, BML regression is associated with decreased knee pain but not a reduced risk of concurrent JSN progression

Early pre-radiographic structural pathology precedes the onset of accelerated knee osteoarthritis.

BACKGROUND: Accelerated knee osteoarthritis (AKOA) is characterized by more pain, impaired physical function, and greater likelihood to receive a joint replacement compared to individuals who develop the typical gradual onset of disease. Prognostic tools are needed to determine which structural pathologies precede the development of AKOA compared to individuals without AKOA. Therefore, the purpose of this manuscript was to determine which pre-radiographic structural features precede the development of AKOA. METHODS: The sample comprised participants in the Osteoarthritis Initiative (OAI) who had at least one radiographically normal knee at baseline (Kellgren-Lawrence [KL] grade  3) and No AKOA. The index visit was the study visit when participants met criteria for AKOA or a matched timepoint for those who did not develop AKOA. Magnetic resonance (MR) images were assessed for 12 structural features at the OAI baseline, and 1 and 2 years prior to the index visit. Separate logistic regression models (i.e. OAI baseline, 1 and 2 years prior) were used to determine which pre-radiographic structural features were more likely to antedate the development of AKOA compared to individuals not developing AKOA. RESULTS: At the OAI baseline visit, degenerative cruciate ligaments (Odds Ratio [OR] = 2.2, 95% Confidence Interval [CI] = 1.3,3.5), infrapatellar fat pad signal intensity alteration (OR = 2.0, 95%CI = 1.2,3.2), medial/lateral meniscal pathology (OR = 2.1/2.4, 95%CI = 1.3,3.4/1.5,3.8), and greater quantitative knee effusion-synovitis (OR = 2.2, 95%CI = 1.4,3.4) were more likely to antedate the development of AKOA when compared to those that did not develop AKOA. These results were similar at one and two years prior to disease onset. Additionally, medial meniscus extrusion at one year prior to disease onset (OR = 3.5, 95%CI = 2.1,6.0) increased the likelihood of developing AKOA. CONCLUSIONS: Early ligamentous degeneration, effusion/synovitis, and meniscal pathology precede the onset of AKOA and may be prognostic biomarkers

Composite quantitative knee structure metrics predict the development of accelerated knee osteoarthritis:data from the osteoarthritis initiative

BACKGROUND: We aimed to determine if composite structural measures of knee osteoarthritis (KOA) progression on magnetic resonance (MR) imaging can predict the radiographic onset of accelerated knee osteoarthritis. METHODS: We used data from a nested case-control study among participants from the Osteoarthritis Initiative without radiographic KOA at baseline. Participants were separated into three groups based on radiographic disease progression over 4 years: 1) accelerated (Kellgren-Lawrence grades [KL] 0/1 to 3/4), 2) typical (increase in KL, excluding accelerated osteoarthritis), or 3) no KOA (no change in KL). We assessed tibiofemoral cartilage damage (four regions: medial/lateral tibia/femur), bone marrow lesion (BML) volume (four regions: medial/lateral tibia/femur), and whole knee effusion-synovitis volume on 3 T MR images with semi-automated programs. We calculated two MR-based composite scores. Cumulative damage was the sum of standardized cartilage damage. Disease activity was the sum of standardized volumes of effusion-synovitis and BMLs. We focused on annual images from 2 years before to 2 years after radiographic onset (or a matched time for those without knee osteoarthritis). To determine between group differences in the composite metrics at all time points, we used generalized linear mixed models with group (3 levels) and time (up to 5 levels). For our prognostic analysis, we used multinomial logistic regression models to determine if one-year worsening in each composite metric change associated with future accelerated knee osteoarthritis (odds ratios [OR] based on units of 1 standard deviation of change). RESULTS: Prior to disease onset, the accelerated KOA group had greater average disease activity compared to the typical and no KOA groups and this persisted up to 2 years after disease onset. During a pre-radiographic disease period, the odds of developing accelerated KOA were greater in people with worsening disease activity [versus typical KOA OR (95% confidence interval [CI]): 1.58 (1.08 to 2.33); versus no KOA: 2.39 (1.55 to 3.71)] or cumulative damage [versus typical KOA: 1.69 (1.14 to 2.51); versus no KOA: 2.11 (1.41 to 3.16)]. CONCLUSIONS: MR-based disease activity and cumulative damage metrics may be prognostic markers to help identify people at risk for accelerated onset and progression of knee osteoarthritis

Bone marrow lesion volume reduction is not associated with improvement of other periarticular bone measures: data from the Osteoarthritis Initiative

Abstract Introduction We evaluated the associations between bone marrow lesion (BML) volume change and changes in periarticular bone mineral density (paBMD) as well as subchondral sclerosis to determine whether BML change is associated with other local bone changes. Methods The convenience sample comprised participants in the Osteoarthritis Initiative (OAI) with weight-bearing posterior-anterior knee radiographs and magnetic resonance images (MRIs) at the 24- and 48-month visits and dual-energy x-ray absorptiometry (DXA) at the 30-/36-month and 48-month visits. The right knee was assessed unless contraindicated for MRI. We used knee DXA scans to measure medial tibia paBMD and medial/lateral paBMD ratio (M:L paBMD). Knee radiographs were scored for sclerosis (grades 0 to 3) in the medial tibia. Two raters determined BML volume on sagittal fat-suppressed MRI by using a semiautomated segmentation method. To focus on knees with only medial tibia BML changes, knees with lateral tibial BMLs were excluded. Medial tibial BML volume change was classified into three groups: BML regression (lowest quartile of medial tibial BML volume change), no-to-minimal change (middle two quartiles), and BML progression (highest quartile). We used proportional odds logistic regression models to evaluate the association between quartiles of changes in medial paBMD or M:L paBMD ratio, as outcomes, and BML volume change. Results The sample (n = 308) included 163 (53%) female subjects, 212 (69%) knees with radiographic osteoarthritis, and participants with a mean age of 63.8 ± 9.3 years and mean body mass index of 29.8 ± 4.7 kg/m2. We found an association between greater increases in medial tibia paBMD and BML regression (OR = 1.7 (95% confidence interval (CI) = 1.1 to 2.8)) and a similar trend for BML progression (OR = 1.6 (95% CI = 1.0 to 2.6]). We also detected associations between greater increase in M:L paBMD and BML regression (OR = 1.6 (95% CI = 1.0 to 2.7]) and BML progression (OR = 1.8 (95% CI = 1.1 to 3.0)), although BML regression had borderline statistical significance. The frequency of sclerosis progression in the medial tibia (n = 14) was greater among knees with BML progression or regression compared with knees without BML change (P = 0.01 and P = 0.04, respectively). Conclusion BML regression and BML progression are characterized by concurrent increases in paBMD and sclerosis, which are characteristic of increased radiographic osteoarthritis severity. At least during 24 months, BML regression is not representative of improvement in other periarticular bone measures

Inflammation and glucose homeostasis are associated with specific structural features among adults without knee osteoarthritis: a cross-sectional study from the osteoarthritis initiative

Background: Greater age and body mass index are strong risk factors for osteoarthritis (OA). Older and overweight individuals may be more susceptible to OA because these factors alter tissue turnover in menisci, articular cartilage, and bone via altered glucose homeostasis and inflammation. Understanding the role of inflammation and glucose homeostasis on structural features of early-stage OA may help identify therapeutic targets to delay or prevent the onset of OA among subsets of adults with these features. We examined if serum concentrations of glucose homeostasis (glucose, glycated serum protein [GSP]) or inflammation (C-reactive protein [CRP]) were associated with prevalent knee bone marrow lesions (BMLs) or effusion among adults without knee OA. Methods: We conducted a cross-sectional study using baseline data from the Osteoarthritis Initiative. We selected participants who had no radiographic knee OA but were at high risk for knee OA. Blinded staff conducted assays for CRP, GSP, and glucose. Readers segmented BML volume and effusion using semi-automated programs. Our outcomes were prevalent BML (knee with a BML volume > 1 cm3) and effusion (knee with an effusion volume > 7.5 cm3). We used logistic regression models with CRP, GSP, or glucose concentrations as the predictors. We adjusted for age, sex, body mass index (BMI), and Physical Activity Scale for the Elderly (PASE) scores. Results: We included 343 participants: mean age = 59 ± 9 years, BMI = 27.9 ± 4.5 kg/m2, PASE score = 171 ± 82, and 64% female. Only CRP was associated with BML prevalence (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09 to 1.87). For effusion, we found an interaction between BMI and CRP: only among adults with a BMI <25 kg/m2 was there a significant trend towards a positive association between CRP and effusion (OR = 1.40, 95% CI = 1.00 to 1.97). We detected a U-shaped relationship between GSP and effusion prevalence. Fasting glucose levels were not significantly associated with the presence of baseline effusion or BML. Conclusions: Among individuals without knee OA, CRP may be related to the presence of BMLs and effusion among normal weight individuals. Abnormal GSP may be associated with effusion. Future studies should explore whether inflammation and glucose homeostasis are predictive of symptomatic knee OA

Quantitative bone marrow lesion size in osteoarthritic knees correlates with cartilage damage and predicts longitudinal cartilage loss

<p>Abstract</p> <p>Background</p> <p>Bone marrow lesions (BMLs), common osteoarthritis-related magnetic resonance imaging findings, are associated with osteoarthritis progression and pain. However, there are no articles describing the use of 3-dimensional quantitative assessments to explore the longitudinal relationship between BMLs and hyaline cartilage loss. The purpose of this study was to assess the cross-sectional and longitudinal descriptive characteristics of BMLs with a simple measurement of approximate BML volume, and describe the cross-sectional and longitudinal relationships between BML size and the extent of hyaline cartilage damage.</p> <p>Methods</p> <p>107 participants with baseline and 24-month follow-up magnetic resonance images from a clinical trial were included with symptomatic knee osteoarthritis. An 'index' compartment was identified for each knee defined as the tibiofemoral compartment with greater disease severity. Subsequently, each knee was evaluated in four regions: index femur, index tibia, non-index femur, and non-index tibia. Approximate BML volume, the product of three linear measurements, was calculated for each BML within a region. Cartilage parameters in the index tibia and femur were measured based on manual segmentation.</p> <p>Results</p> <p>BML volume changes by region were: index femur (median [95% confidence interval of the median]) 0.1 cm³(-0.5 to 0.9 cm³), index tibia 0.5 cm³(-0.3 to 1.7 cm³), non-index femur 0.4 cm³(-0.2 to 1.6 cm³), and non-index tibia 0.2 cm³(-0.1 to 1.2 cm³). Among 44 knees with full thickness cartilage loss, baseline tibia BML volume correlated with baseline tibia full thickness cartilage lesion area (<it>r </it>= 0.63, <it>p</it>< 0.002) and baseline femur BML volume with longitudinal change in femoral full thickness cartilage lesion area (<it>r </it>= 0.48 <it>p</it>< 0.002).</p> <p>Conclusions</p> <p>Many regions had no or small longitudinal changes in approximate BML volume but some knees experienced large changes. Baseline BML size was associated to longitudinal changes in area of full thickness cartilage loss.</p

Ultrasonic Measurement of Stress in SLM 316L Stainless Steel Forming Parts Manufactured Using Different Scanning Strategies

Selective Laser Melting (SLM) technology is a new kind of additive manufacturing technology developed in in the last decade. Measurement and control of stress in metal forming layer is the basic problem of SLM forming parts. Critical Refraction Longitudinal (LCR) wave method was used to measure stress. The acoustic-elastic formulas for measuring stresses in SLM 316L stainless steel forming parts manufactured using meander, stripe, and chess board scanning strategies, respectively, were established based on static load tensile test. The experimental results show that the acoustic time difference of LCR wave in SLM specimen manufactured with 316L stainless steel increases linearly with the increase of stress when the tensile stress is less than critical stress (372 MPa, 465 MPa, and 494 MPa). Due to the inhomogeneous deformation of the anisotropic SLM forming layer and the dimple-micropore aggregation fracture mechanism, the acousto-elastic curve fluctuates up and down along the irregular curve when the tensile stress is larger than critical stress. The results of corroboration experiments show that nondestructive measurement of stress in SLM forming specimen can be realized by using LCR wave method. The scanning strategy can significantly affect the tensile strength and yield strength of SLM forming specimen. The stresses were all in tension stress state at the edge of the specimens, whatever scanning strategy was used. Sub-area scanning and scanning sequence of alternate and intersect were adopted, which can effectively reduce the stress in the SLM forming specimen. The overall stress values of SLM forming specimen manufactured using chess board scanning strategy were smaller than that using meander and stripe strategies. The distribution of stress were more uniform