Data-Driven Definitions for Active and Structural MRI Lesions in the Sacroiliac Joint in Spondyloarthritis and their Predictive Utility

OBJECTIVES: To determine quantitative sacroiliac joint (SIJ) MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial spondyloarthritis (axSpA) and that predict clinical diagnosis. METHODS: The ASAS MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises: A. 169 cases and 7 central readers; B. 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SIJ quadrants or slices with bone marrow edema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with ≥95% specificity were analyzed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPV/NPV) and selecting cut-offs with PPV≥95%. RESULTS: Active or structural lesions typical of axSpA on MRI had PPV≥95% for clinical diagnosis of axSpA. Cut-offs that best reflect definite active lesion typical of axSpA were either ≥4 SIJ quadrants with BME at any location or at the same location in ≥ 3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of ≥ 3 SIJ quadrants with erosion or ≥ 5 with fat lesion, erosion at the same location for ≥2 consecutive slices, fat lesion at the same location for ≥3 consecutive slices, or presence of a 'deep' (>1cm) fat lesion. CONCLUSION: We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPV for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research

Elephant (Loxodonta africana) Home Ranges in Sabi Sand Reserve and Kruger National Park: A Five-Year Satellite Tracking Study

During a five-year GPS satellite tracking study in Sabi Sand Reserve (SSR) and Kruger National Park (KNP) we monitored the daily movements of an elephant cow (Loxodonta africana) from September 2003 to August 2008. The study animal was confirmed to be part of a group of seven elephants therefore her position is representative of the matriarchal group. We found that the study animal did not use habitat randomly and confirmed strong seasonal fidelity to its summer and winter five-year home ranges. The cow's summer home range was in KNP in an area more than four times that of her SSR winter home range. She exhibited clear park habitation with up to three visits per year travelling via a well-defined northern or southern corridor. There was a positive correlation between the daily distance the elephant walked and minimum daily temperature and the elephant was significantly closer to rivers and artificial waterholes than would be expected if it were moving randomly in KNP and SSR. Transect lines established through the home ranges were surveyed to further understand the fine scale of the landscape and vegetation representative of the home ranges

Resolving the paradox of shame: differentiating among specific appraisal-feeling combinations explains pro-social and self-defensive motivation

Research has shown that people can respond both self-defensively and pro-socially when they experience shame. We address this paradox by differentiating among specific appraisals (of specific self-defect and concern for condemnation) and feelings (of shame, inferiority, and rejection) often reported as part of shame. In two Experiments (Study 1: N = 85; Study 2: N = 112), manipulations that put participants’ social-image at risk increased their appraisal of concern for condemnation. In Study 2, a manipulation of moral failure increased participants’ appraisal that they suffered a specific self-defect. In both studies, mediation analyses showed that effects of the social-image at risk manipulation on self-defensive motivation were explained by appraisal of concern for condemnation and felt rejection. In contrast, the effect of the moral failure manipulation on pro-social motivation in Study 2 was explained by appraisal of a specific self-defect and felt shame. Thus, distinguishing among the appraisals and feelings tied to shame enabled clearer prediction of pro-social and self-defensive responses to moral failure with and without risk to social-image

⁸⁹Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

Background: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 ( 89Zr)-labeled pembrolizumab before PD-1 antibody treatment. Patients and methods: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUV max) and expressed as geometric mean. Normal organ uptake was calculated as SUV mean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. Results: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUV max did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUV mean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. Conclusion: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation

MRI lesions in the sacroiliac joints of patients with spondyloarthritis: an update of definitions and validation by the ASAS MRI working group

OBJECTIVES: The Assessment of SpondyloArthritis international Society (ASAS) MRI working group (WG) was convened to generate a consensus update on standardised definitions for MRI lesions in the sacroiliac joint (SIJ) of patients with spondyloarthritis (SpA), and to conduct preliminary validation. // METHODS: The literature pertaining to these MRI lesion definitions was discussed at three meetings of the group. 25 investigators (20 rheumatologists, 5 radiologists) determined which definitions should be retained or required revision, and which required a new definition. Lesion definitions were assessed in a multi-reader validation exercise using 278 MRI scans from the ASAS classification cohort by global assessment (lesion present/absent) and detailed scoring (inflammation and structural). Reliability of detection of lesions was analysed using kappa statistics and the intraclass correlation coefficient (ICC). // RESULTS: No revisions were made to the current ASAS definition of a positive SIJ MRI or definitions for subchondral inflammation and sclerosis. The following definitions were revised: capsulitis, enthesitis, fat lesion and erosion. New definitions were developed for joint space enhancement, joint space fluid, fat metaplasia in an erosion cavity, ankylosis and bone bud. The most frequently detected structural lesion, erosion, was detected almost as reliably as subchondral inflammation (κappa/ICC:0.61/0.54 and 0.60/0.83) . Fat metaplasia in an erosion cavity and ankylosis were also reliably detected despite their low frequency (κappa/ICC:0.50/0.37 and 0.58/0.97). // CONCLUSION: The ASAS-MRI WG concluded that several definitions required revision and some new definitions were necessary. Multi-reader validation demonstrated substantial reliability for the most frequently detected lesions and comparable reliability between active and structural lesions

Data-driven definitions for active and structural MRI lesions in the sacroiliac joint in spondyloarthritis and their predictive utility

Objectives. To determine quantitative SI joint MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial SpA (axSpA) and that predict clinical diagnosis.Methods. The Assessment of SpondyloArthritis international Society (ASAS) MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises where (A) 169 cases and 7 central readers; (B) 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SI joint quadrants or slices with bone marrow oedema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with >= 95% specificity were analysed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPVs/NPVs) and selecting cut-offs with PPV >= 95%.Results. Active or structural lesions typical of axSpA on MRI had PPVs >= 95% for clinical diagnosis of axSpA. Cut-offs that best reflected a definite active lesion typical of axSpA were either >= 4 SI joint quadrants with BME at any location or at the same location in >= 3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of >= 3 SI joint quadrants with erosion or >= 5 with fat lesions, erosion at the same location for >= 2 consecutive slices, fat lesions at the same location for >= 3 consecutive slices, or presence of a deep (i.e. >1 cm depth) fat lesion.Conclusion. We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPVs for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research.Pathophysiology and treatment of rheumatic disease

Risk and Ethical Concerns of Hunting Male Elephant: Behavioural and Physiological Assays of the Remaining Elephants

BACKGROUND: Hunting of male African elephants may pose ethical and risk concerns, particularly given their status as a charismatic species of high touristic value, yet which are capable of both killing people and damaging infrastructure. METHODOLOGY/PRINCIPAL FINDINGS: We quantified the effect of hunts of male elephants on (1) risk of attack or damage (11 hunts), and (2) behavioural (movement dynamics) and physiological (stress hormone metabolite concentrations) responses (4 hunts) in Pilanesberg National Park. For eleven hunts, there were no subsequent attacks on people or infrastructure, and elephants did not break out of the fenced reserve. For three focal hunts, there was an initial flight response by bulls present at the hunting site, but their movements stabilised the day after the hunt event. Animals not present at the hunt (both bulls and herds) did not show movement responses. Physiologically, hunting elephant bulls increased faecal stress hormone levels (corticosterone metabolites) in both those bulls that were present at the hunts (for up to four days post-hunt) and in the broader bull and breeding herd population (for up to one month post-hunt). CONCLUSIONS/SIGNIFICANCE: As all responses were relatively minor, hunting male elephants is ethically acceptable when considering effects on the remaining elephant population; however bulls should be hunted when alone. Hunting is feasible in relatively small enclosed reserves without major risk of attack, damage, or breakout. Physiological stress assays were more effective than behavioural responses in detecting effects of human intervention. Similar studies should evaluate intervention consequences, inform and improve best practice, and should be widely applied by management agencies

To Be or Not to Be a Flatworm: The Acoel Controversy

Since first described, acoels were considered members of the flatworms (Platyhelminthes). However, no clear synapomorphies among the three large flatworm taxa - the Catenulida, the Acoelomorpha and the Rhabditophora - have been characterized to date. Molecular phylogenies, on the other hand, commonly positioned acoels separate from other flatworms. Accordingly, our own multi-locus phylogenetic analysis using 43 genes and 23 animal species places the acoel flatworm Isodiametra pulchra at the base of all Bilateria, distant from other flatworms. By contrast, novel data on the distribution and proliferation of stem cells and the specific mode of epidermal replacement constitute a strong synapomorphy for the Acoela plus the major group of flatworms, the Rhabditophora. The expression of a piwi-like gene not only in gonadal, but also in adult somatic stem cells is another unique feature among bilaterians. These two independent stem-cell-related characters put the Acoela into the Platyhelminthes-Lophotrochozoa clade and account for the most parsimonious evolutionary explanation of epidermal cell renewal in the Bilateria. Most available multigene analyses produce conflicting results regarding the position of the acoels in the tree of life. Given these phylogenomic conflicts and the contradiction of developmental and morphological data with phylogenomic results, the monophyly of the phylum Platyhelminthes and the position of the Acoela remain unresolved. By these data, both the inclusion of Acoela within Platyhelminthes, and their separation from flatworms as basal bilaterians are well-supported alternatives

Redirecting T Cells to Ewing's Sarcoma Family of Tumors by a Chimeric NKG2D Receptor Expressed by Lentiviral Transduction or mRNA Transfection

We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8pos and also CD4pos cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection

Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation

A major therapeutic challenge is how to replace bone once it is lost. Bone loss is a characteristic of chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. Cells and cytokines of the immune system are known to regulate bone turnover by controlling the differentiation and activity of osteoclasts, the bone resorbing cells. However, less is known about the regulation of osteoblasts (OB), the bone forming cells. This study aimed to investigate whether immune cells also regulate OB differentiation. Using in vitro cell cultures of human bone marrow-derived mesenchymal stem cells (MSC), it was shown that monocytes/macrophages potently induced MSC differentiation into OBs. This was evident by increased alkaline phosphatase (ALP) after 7 days and the formation of mineralised bone nodules at 21 days. This monocyte-induced osteogenic effect was mediated by cell contact with MSCs leading to the production of soluble factor(s) by the monocytes. As a consequence of these interactions we observed a rapid activation of STAT3 in the MSCs. Gene profiling of STAT3 constitutively active (STAT3C) infected MSCs using Illumina whole human genome arrays showed that Runx2 and ALP were up-regulated whilst DKK1 was down-regulated in response to STAT3 signalling. STAT3C also led to the up-regulation of the oncostatin M (OSM) and LIF receptors. In the co-cultures, OSM that was produced by monocytes activated STAT3 in MSCs, and neutralising antibodies to OSM reduced ALP by 50%. These data indicate that OSM, in conjunction with other mediators, can drive MSC differentiation into OB. This study establishes a role for monocyte/macrophages as critical regulators of osteogenic differentiation via OSM production and the induction of STAT3 signalling in MSCs. Inducing the local activation of STAT3 in bone cells may be a valuable tool to increase bone formation in osteoporosis and arthritis, and in localised bone remodelling during fracture repair