Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a+ senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the “benign” senescent cells that surround and support AML.

Judgments made by the assessors observing consultations are widely used in the assessment of medical students. The aim of this research was to study judgment accuracy and confidence and the relationship between these. Assessors watched recordings of consultations, scoring the students on: a checklist of items; attributes of consultation; a passmark scale and lastly their confidence in this last judgment. Then they were interviewed using stimulated recall to explain their rationale for scoring and confidence. Twenty-three staff assessors watched two consultations. Assessor confidence and accuracy were least for those student performances perceived near the passmark standard. The difference between confidence and accuracy, over-confidence, was greatest at this level, although at the extremes under-confidence was found. In the interviews the assessors were aware of a variety of factors that they perceived affected their scoring and confidence. As in other contexts confidence and accuracy vary and over-confidence increases the more difficult the judgments. However, this study also demonstrated under-confidence for less difficult judgments. The perception that more information would help, may improve confidence but not necessarily accuracy, so increasing over-confidence.

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Purpose It has previously been suggested that failure to achieve 70% metaphyseal fit with the Austin Moore prosthesis predisposes to subsidence and failure of the prosthesis secondary to stem loosening. We performed a radiological review to test this hypothesis, and determine whether a correlation existed between head size and metaphyseal fit of the uncemented Austin Moore hip prosthesis. Methods Post-operative radiographs of 102 uncemented Austin Moore hemiarthroplasty patients were retrospectively reviewed. Three observers blinded to the head size of the prosthesis, measured the percentage metaphyseal fit of each stem, using a previously published technique. Results Eighty-six females and 16 males were included in this study. Eighteen of the radiographs were excluded for incorrect implantation, narrow stem insertion, and un-interpretable post-operative radiographs. Implants with a head size of 42 mm had an average metaphyseal fit of 84.5%. Those with head size 54 mm had only a 56% metaphyseal fit. The result was strongly associated with an R value of −0.93. Conclusion We have shown an inverse correlation exists between prosthesis head size and metaphyseal fit. Austin Moore prostheses with head sizes greater than 49 mm are likely to be loose from the moment of insertion. This poses a particular risk in men. In our study, only one male required prosthesis with a head less than 49 mm. In these patients, use of an alternative prosthesis such as a bipolar uncemented or cemented hemiarthroplasty is recommended.