Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34 − Flt3 − KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34 − Flt3 − KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the upregulation of angiocrine factors, with Akt-mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs.Acute injury to the bone marrow microenvironment, after treatment with chemotherapy and irradiation, or myelotoxin, suppresses haematopoiesis, which results in the depletion of HSPCs and the development of life-threatening pancytopenias. The interaction of the surviving HSPCs with the bone marrow niche cells rapidly reconstitutes haematopoiesis, rescuing the host from complications associated with long-term bone marrow suppression. Bone marrow niches orchestrate maintenance, expansion and trafficking of HSPCs [1][2][3][4][5] . The osteogenic niche modulates the quiescence of the HSPCs 1-2 , whereas the vascular niche, demarcated by the bone marrow sinusoidal endothelial cells (SECs), regenerates and replenishes the HSPC Results Endothelial cells support both self-renewal and lineage-specific differentiation of HSPCsStudying the role of primary human endothelial cells (PECs) in the regulation of haematopoiesis has been hampered by the need for growthfactor deprivation during culture, which leads to apoptosis of PECs. Supplementation with serum and angiogenic factors, such as VEGF-A and basic-fibroblast growth factor (FGF2), are therefore necessary to maintain PECs for co-culture with HSPCs. However, serum inhibits the self-renewal of HSPCs, whereas FGF2 promotes self-renewal of HSPCs 16 , rendering it difficult to assess the cell-autonomous capacity of PECs to support HSPC homeostasis. To circumvent this problem, PECs can be transduced with an adenovirus gene, early region 4 encoded open reading frame-1 (E4ORF1), which leads to constitutive activation of Akt and enables co-culturing of PECs with HSPCs in serum-and growth factor-free medium for weeks, while maintaining their angio...

Background Successful return to work after stroke may improve economic circumstances, quality of life and overall life satisfaction, but not all stroke survivors are able to return to work. Aim Our aim was to determine what proportion of previously employed patients return to work after an acute stroke resulting in mild to moderate disability and to examine factors associated with a successful return to work. Methods Patients 18–60 years of age who were previously employed and who had a first‐ever stroke 3 months to 2 years previously resulting in mild to moderate disability (modified Rankin score ≤3) were recruited. Socio‐demographic and clinical information was collected and anxiety, depression and social support were assessed using previously validated instruments. Multivariate logistic regression was used to assess factors associated with a successful return to work. Results Of 141 patients (mean age ± SD 48 ± 8.8 years), 74 (52.5%) returned to work after stroke. Multivariate analysis demonstrated that a lower modified Rankin scale at 3 months [odds ratio (OR) 3.70, 95% confidence interval (CI) 1.77–7.76], younger age (OR 2.24, 95% CI 1.07–4.67) and a professional or business job (OR 3.02, 95% CI 1.44–6.34) were significantly associated with successful return to work and revealed that anxiety, depression and social support score did not affect patients' decision to return to work (P = 0.17, 0.61 and 0.27, respectively). Conclusions Amongst patients with mild to moderate disability after stroke, almost half do not return to work, and this is determined by functional disability and type of job rather than psychosocial factors such as anxiety and depression.

Background: Opioid use is a public health crisis in the United States and an area of increased focus in orthopaedic surgery. The aim of this study is to investigate whether preoperative opioid use had any effect on patient-reported outcome measures (PROMs) before and after total hip arthroplasty (THA). Methods: A total of 389 patients with THA with both preoperative and postoperative PROMs were reviewed: (1) 76 patients with preoperative opioid use (24%) and (2) 237 patients without preoperative opioid use (76%). Patient demographics and clinical information including opioid use, length of stay, and implant information.Results: Preoperative opioid users were more likely to stay in the hospital longer (P = 0.004) and be discharged to a rehabilitation facility (P = 0.038). Postoperatively, the Physical Function Short Form 10a (P = 0.021) and Patient-Reported Outcomes Measurement Information System Global-10 (P , 0.001 physical, P = 0.001, mental) were significantly lower in the preoperative opioid users. Within groups, both nonusers and preoperative opioid users saw improvements after THA in Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form (P , 0.001), Short Form 10a (P , 0.001), and Patient-Reported Outcomes Measurement Information System Global-10 (P , 0.001, physical and P = 0.008, mental). Discussion: Although all patients reported improvements after THA regardless of preoperative opioid use, preoperative opioid users undergoing THA had significantly lower patient-reported outcome scores, longer hospital stays, and a more likely discharge to rehabilitation.B eginning with the initiation of the American Pain Society "Pain, The Fifth Vital Sign" campaign in the 1990s and the subsequent mandate by the Joint Commission on the Accreditation of Healthcare Organizations to provide pain assessment and treatment for all patients in ac-credited healthcare settings, an opioid epidemic has risen in the United States. 1 Opioid use is the leading cause of accidental death in the United States, and more than 2.4 million Americans have a severe opioid use disorder. 2 Consequently, increasing focus has been placed on