Aims: To determine the effect of transplantation of undifferentiated and cardiac pre-differentiated adipose stem cells compared with bone marrow mononuclear cells (BM-MNC) in a chronic model of myocardial infarction. Methods: Ninety-five Sprague-Dawley rats underwent left coronary artery ligation and after 1 month received by direct intramyocardial injection either adipose derived stem cells (ADSC), cardiomyogenic cells (AD-CMG) or BM-MNC from enhanced-Green Fluorescent Protein (eGFP) mice. The control group was treated with culture medium. Heart function was assessed by echocardiography and 18 F-FDG microPET. Cell engraftment, differentiation, angiogenesis and fibrosis in the scar tissue were also evaluated by (immuno)histochemistry and immunofluorescence. Results: One month after cell transplantation, ADSC induced a significant improvement in heart function (LVEF 46.3 ± 9.6% versus 27.7 ± 8% pre-transplant) and tissue viability (64.78 ± 7.2% versus 55.89 ± 6.3% pre-transplant). An increase in the degree of angiogenesis and a decrease in fibrosis were also detected. Although transplantation of AD-CMG or BM-MNC also had a positive, albeit smaller, effect on angiogenesis and fibrosis in the infarcted hearts, this benefit did not translate into a significant improvement in heart function or tissue viability. Conclusion: These results indicate that transplantation of adipose derived cells in chronic infarct provides a superior benefit to cardiac predifferentiated ADSC and BM-MNC.

Cardiomyogenic cells can be selected and expanded in large amounts from mouse adipose tissue. They can survive and differentiate in an acute myocardial infarction model, avoiding remodelling and impairment of cardiac function, and can promote neo-vascularization in the ischaemic heart.

We aimed to compare serum biomarkers of inflammation, redox status and cartilage degradation between chronic low back pain (cLBP) patients with and without Modic 1 changes. We used a convenience sample of patients recruited from a single center, case-control study, conducted in a tertiary care center. From December, 2014 to May, 2016, 2,292 patients were consecutively screened, 34 met inclusion criteria and were prospectively enrolled in the present study. Cases (n = 13) were defined as patients with Modic 1 changes detected on MRI and controls (n = 21) as cLBP patients without (Modic 0). To assess serum biomarkers of inflammation, redox status and cartilage degradation, fasting serum samples were collected in a standardized manner and analyzed by immunoassays and spectrophotometry. Mean (95% CI) age was 44.1 (40.0–48.1) years and mean LBP duration was 72.5 (53.0–91.9) months. Serum biomarkers of inflammation (IL-1β, IL-6, IL-8 and TNF-α), redox status (total thiols, advanced oxidation protein products and carbonyl groups) and cartilage degradation (Coll2-1 and Coll2-1NO 2 ) did not differ between cLBP patients with and without Modic 1 changes. In summary, we did not find any differences in serum biomarkers between cLBP patients with and without Modic 1 changes. Interpretation is limited by convenience sampling and small sample size.

Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T-cells. Long-term remissions are rare in CTCL, and the pathophysiology of long-lasting disease control is unknown. Mogamulizumab is a defucosylated anti-human CCR4 antibody that depletes CCR4-expressing CTCL tumor cells and peripheral blood memory regulatory T cells. Prolonged remissions and immune side effects have been observed in mogamulizumab-treated CTCL patients. We report that mogamulizumab induced skin rashes in 32% of 44 CTCL patients. These rashes were associated with long-term CTCL remission, even in the absence of specific CTCL treatment. CTCL patients with mogamulizumab-induced rash had significantly higher overall survival (hazard ratio, 0.16 (0.04-0.73, p=0.01)). Histopathology and immunohistochemistry of the rashes revealed granulomatous and lichenoid patterns with CD163 macrophagic and CD8 T-cell infiltrates. Depletion of skin CTCL cells was confirmed by high-throughput sequencing analysis of TCRβ genes and in blood by flow cytometry. New reactive T-cell clones were recruited in skin. Gene expression analysis showed overexpression of CXCL9 and CXCL11, two chemokines involved in CXCR3-expressing T-cell homing to skin. Single-cell RNA sequencing analysis in skin of CTCL patients confirmed that CXCL9 and CXCL11 were primarily macrophage-derived and that skin T-cells expressed CXCR3. Finally, patients with rashes had a significantly higher proportion of exhausted reactive blood T-cells expressing TIGIT and PD1 at baseline compared to patients without rash, which decreased under mogamulizumab treatment, consistent with an activation of the antitumor immunity. Together, these data suggest that mogamulizumab may induce long-term immune control in CTCL patients by activation of the macrophagic and T-cell immune responses.

In the late 1980s, the description by Modic and colleagues of elementary discovertebral changes detected on MRI (Modic classification) suggested for the first time a possible correlation between anatomical and clinical features in a subgroup of patients with non-specific chronic low back pain. Degenerative disc disease is frequent and usually asymptomatic, but Modic 1 changes in the vertebral endplates adjacent to a degenerated disc are associated with inflammatory-like chronic low back pain and low-grade local and systemic inflammation, which led to the concept of ‘active discopathy’. Active discopathy shares some similarities with acute flares of peripheral osteoarthritis. Likewise, what triggers disc activation and how it self-limits remain unknown. A better understanding of mechanisms underlying disc activation and its self-limitation is of clinical relevance because it may enable the design of more targeted pharmacological and non-pharmacological interventions for the subgroup of patients with chronic low back pain and active discopathy. Here, we narratively review current disc-centred biomechanical and biochemical hypotheses of disc activation and discuss evidence of interactions with adverse personal and environmental factors.

IMPORTANCE Osteopathic manipulative treatment (OMT) is frequently offered to people with nonspecific low back pain (LBP) but never compared with sham OMT for reducing LBP-specific activity limitations.OBJECTIVE To compare the efficacy of standard OMT vs sham OMT for reducing LBP-specific activity limitations at 3 months in persons with nonspecific subacute or chronic LBP. DESIGN, SETTING, AND PARTICIPANTSThis prospective, parallel-group, single-blind, single-center, sham-controlled randomized clinical trial recruited participants with nonspecific subacute or chronic LBP from a tertiary care center in

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definition of publication was publication of results either in peer-reviewed journals or on ClinicalTrials.gov; our secondary definition was publication in peer-reviewed journals. Variables included in our model (Table 1) were determined a priori.Overall, 141 RCTs met our inclusion criteria. Sixteen RCTs (11%), with 4904 participants, were discontinued prematurely. Reasons included business or sponsor decision (n = 7), insufficient patient recruitment (n = 4) and administration or conduct problems (n = 1). Four RCTs did not provide a reason for discontinuation. Unblinded RCTs (vs. RCTs with blinding of any sort) were significantly more likely to be discontinued (OR 16Á7, 95% CI 2Á22-125) (Table 1).In total, 104 RCTs (74%) met our primary definition of publication, including 93 published in peer-reviewed journals. RCTs investigating topical treatments were significantly more likely to result in nonpublication of results in the multivariable analysis using our primary definition of publication (OR 24Á2, 95% CI 1.14-516) (Table 1), as well as our secondary definition of publication (OR 14Á7, 95% CI 1Á17-185). Discontinued RCTs were associated with nonpublication in the univariable analysis, but this association was attenuated when adjusted for additional factors (OR 4Á50, 95% CI 0Á74-27Á4).In this study of phase III RCTs of psoriasis treatments, 11% of the RCTs were discontinued prematurely, a rate lower than reported in other areas of medicine. [2][3][4] Half of the discontinued RCTs did not cite a reason for discontinuation, and for those that did, the lack of semantic standardization for reasons for discontinuation listed on ClinicalTrials.gov leads to ambiguity and predisposes to misinterpretation. Over a quarter of psoriasis RCTs did not publish their results in peer-reviewed journals or on ClinicalTrials.gov, which is consistent with RCTs in other areas of medicine. 2,3 Topical intervention was the only factor significantly associated with increased nonpublication following adjustment for additional variables. A report on ClinicalTrials.gov for Janus kinase inhibitor therapy suggested that the nonpublication of trials for topical interventions may be related to a lack of efficacy, as many were discontinued due to inefficacy or futility. 5 These findings may also be explained by the increased emphasis in the literature on the evolving systemic treatment landscape.Our study limitations include potential inaccuracies or missing data in trial registry entries, although trial data undergo quality control via automated checks and manual review by ClinicalTrials.gov staff. Our statistical analyses were also limited by the small number of events for certain variables, with inadequate statistical power to assess associations thus limiting interpretation of results.The nonpublication of RCTs of psoriasis remains prevalent. Insight into challenges that prevent RCTs from reaching completion is limited by the lack of reporting of reasons for discontinuation on trial registries. Reporting of reasons for discontinuation on t...