Quantifying the Tibiofemoral Joint Space Using X-ray Tomosynthesis

Purpose: Digital x-ray tomosynthesis (DTS) has the potential to provide 3D information about the knee joint in a load-bearing posture, which may improve diagnosis and monitoring of knee osteoarthritis compared with projection radiography, the current standard of care. Manually quantifying and visualizing the joint space width (JSW) from 3D tomosynthesis datasets may be challenging. This work developed a semiautomated algorithm for quantifying the 3D tibiofemoral JSW from reconstructed DTS images. The algorithm was validated through anthropomorphic phantom experiments and applied to three clinical datasets. Methods: A user-selected volume of interest within the reconstructed DTS volume was enhanced with 1D multiscale gradient kernels. The edge-enhanced volumes were divided by polarity into tibial and femoral edge maps and combined across kernel scales. A 2D connected components algorithm was performed to determine candidate tibial and femoral edges. A 2D joint space width map (JSW) was constructed to represent the 3D tibiofemoral joint space. To quantify the algorithm accuracy, an adjustable knee phantom was constructed, and eleven posterior–anterior (PA) and lateral DTS scans were acquired with the medial minimum JSW of the phantom set to 0–5 mm in 0.5 mm increments (VolumeRadTM, GE Healthcare, Chalfont St. Giles, United Kingdom). The accuracy of the algorithm was quantified by comparing the minimum JSW in a region of interest in the medial compartment of the JSW map to the measured phantom setting for each trial. In addition, the algorithm was applied to DTS scans of a static knee phantom and the JSW map compared to values estimated from a manually segmented computed tomography (CT) dataset. The algorithm was also applied to three clinical DTS datasets of osteoarthritic patients. Results: The algorithm segmented the JSW and generated a JSW map for all phantom and clinical datasets. For the adjustable phantom, the estimated minimum JSW values were plotted against the measured values for all trials. A linear fit estimated a slope of 0.887 (R2¼0.962) and a mean error across all trials of 0.34 mm for the PA phantom data. The estimated minimum JSW values for the lateral adjustable phantom acquisitions were found to have low correlation to the measured values (R2¼0.377), with a mean error of 2.13 mm. The error in the lateral adjustable-phantom datasets appeared to be caused by artifacts due to unrealistic features in the phantom bones. JSW maps generated by DTS and CT varied by a mean of 0.6 mm and 0.8 mm across the knee joint, for PA and lateral scans. The tibial and femoral edges were successfully segmented and JSW maps determined for PA and lateral clinical DTS datasets. Conclusions: A semiautomated method is presented for quantifying the 3D joint space in a 2D JSW map using tomosynthesis images. The proposed algorithm quantified the JSW across the knee joint to sub-millimeter accuracy for PA tomosynthesis acquisitions. Overall, the results suggest that x-ray tomosynthesis may be beneficial for diagnosing and monitoring disease progression or treatment of osteoarthritis by providing quantitative images of JSW in the load-bearing knee

Radiation dosimetry in digital breast tomosynthesis: Report of AAPM Tomosynthesis Subcommittee Task Group 223

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134828/1/mp2600.pd

Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma

Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades N-arginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/ sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib (Btz) by increasing: i) killing of human MM cells by stimulating both Btz-mediated apoptosis and necroptosis, a process regulated by p62; and ii) preservation of bone mass by stimulating osteoblast differentiation and inhibiting osteoclastic bone destruction. Co-administration of Btz and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, co-administration of Btz and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti- MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health

Genetic turnovers and northern survival during the last glacial maximum in European brown bears.

The current phylogeographic pattern of European brown bears (Ursus arctos) has commonly been explained by postglacial recolonization out of geographically distinct refugia in southern Europe, a pattern well in accordance with the expansion/contraction model. Studies of ancient DNA from brown bear remains have questioned this pattern, but have failed to explain the glacial distribution of mitochondrial brown bear clades and their subsequent expansion across the European continent. We here present 136 new mitochondrial sequences generated from 346 remains from Europe, ranging in age between the Late Pleistocene and historical times. The genetic data show a high Late Pleistocene diversity across the continent and challenge the strict confinement of bears to traditional southern refugia during the last glacial maximum (LGM). The mitochondrial data further suggest a genetic turnover just before this time, as well as a steep demographic decline starting in the mid-Holocene. Levels of stable nitrogen isotopes from the remains confirm a previously proposed shift toward increasing herbivory around the LGM in Europe. Overall, these results suggest that in addition to climate, anthropogenic impact and inter-specific competition may have had more important effects on the brown bear's ecology, demography, and genetic structure than previously thought

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Extended model of the photoinitiation mechanisms in photopolymer materials

In order to further improve photopolymer materials for applications such as data storage, a deeper understanding of the photochemical mechanisms which are present during the formation of holographic gratings has become ever more crucial. This is especially true of the photoinitiation processes, since holographic data storage requires multiple sequential short exposures. Previously, models describing the temporal variation in the photosensitizer (dye)concentration as a function of exposure have been presented and applied to two different types of photosensitizer, i.e., Methylene Blue and Erythrosine B, in a polyvinyl alcohol/acrylamide based photopolymer. These models include the effects of photosensitizer recovery and bleaching under certain limiting conditions. In this paper, based on a detailed study of the photochemical reactions, the previous models are further developed to more physically represent these effects. This enables a more accurate description of the time varying dye absorption, recovery, and bleaching, and therefore of the generation of primary radicals in photopolymers containing such dyes.Science Foundation IrelandIrish Research Council for Science, Engineering and TechnologyOther funderEnterprise Irelandpe, la, sp, ke, is, en - TS 06.12.1

Modeling the photochemical effects present during holographic grating formation in photopolymer materials

The development of a theoretical model of the processes present during the formation of a holographic grating in photopolymer materials is crucial in enabling further development of holographic applications. To achieve this, it is necessary to understand the photochemical and photophysical processes involved and to isolate their effects, enabling each to be modeled accurately. While photopolymer materials are practical materials for use as holographic recording media, understanding the recording mechanisms will allow their limitations for certain processes to be overcome. In this paper we report generalizations of the nonlocal polymer driven diffusion (NPDD) model to include the effects of photosensitive dye absorption and the inhibition effects.Science Foundation IrelandIrish Research Council for Science, Engineering and TechnologyOther funderEnterprise IrelandInternational Society for Optical Engineering (SPIE)pe, la, sp, ke, st, en - kpw22/12/1

Improvement of the spatial frequency response of photopolymer materials by modifying polymer chain length

One of the key predictions of the nonlocal photopolymerization driven diffusion (NPDD) model is that a reduction in the extent of the nonlocal effects within a material will improve the high spatial frequency response. The NPDD model is generalized to more accurately model material absorbtivity. By eliminating the necessity for the steady-state approximation to describe the rate of change of monomer radical concentration, a more accurate physical representation of the initial transient behavior, at the start of grating growth, is achieved, which includes the effects of oxygen-based inhibition. The spatial frequency response of an acrylamide/polyvinylalcohol-based photopolymer is then improved through the addition of a chain transfer agent (CTA), sodium formate. Using the NPDD model demonstrates that the CTA has the effect of decreasing the average length of the polyacrylamide (PA) chains formed, thus reducing the nonlocal response parameter, σ. Further independent confirmation of the resulting reduction in the PA average molecular weight is provided using a diffusion-based holographic techniqueScience Foundation IrelandIrish Research Council for Science, Engineering and TechnologySPIE Educational ScholarshipEnterprise Irelandpu, pe, la, sp, ke, ab, is, en - kpw16/11/1

Improvement of the spatial frequency response of photopolymer materials by modifying polymer chain length

One of the key predictions of the nonlocal photopolymerization driven diffusion (NPDD) model is that a reduction in the extent of the nonlocal effects within a material will improve the high spatial frequency response. The NPDD model is generalized to more accurately model material absorbtivity. By eliminating the necessity for the steady-state approximation to describe the rate of change of monomer radical concentration, a more accurate physical representation of the initial transient behavior, at the start of grating growth, is achieved, which includes the effects of oxygen-based inhibition. The spatial frequency response of an acrylamide/polyvinylalcohol-based photopolymer is then improved through the addition of a chain transfer agent (CTA), sodium formate. Using the NPDD model demonstrates that the CTA has the effect of decreasing the average length of the polyacrylamide (PA) chains formed, thus reducing the nonlocal response parameter, σ. Further independent confirmation of the resulting reduction in the PA average molecular weight is provided using a diffusion-based holographic techniqueScience Foundation IrelandIrish Research Council for Science, Engineering and TechnologySPIE Educational ScholarshipEnterprise Irelandpu, pe, la, sp, ke, ab, is, en - kpw16/11/1