Citations

The aim of this study was to characterise a recently identified adult smooth muscle stem-like/progenitor cell (SMSPC) and exploit the ability to differentiate contractile smooth muscle cells (SMC) from SMSPCs facilitating tissue engineering of small to medium arteries, an approach which is hampered by inadequate sources of, and scale up methodologies for autologous SMCs. We initially identified a novel SMSPC in the bone marrow (BM) of rats that retained classic stem cell-like characteristics (clonogenicity, unlimited self-renewal, high telomerase activity, expression of stem cell markers) whilst expressing low levels of SMC-like transcripts. Spontaneous differentiation favoured a SMC phenotype where ~20-fold increases in calponin and SM-MHC protein expression were observed 10 days post-embryoid body formation, an effect augmented by TGFβ (P < 0.0001). Differentiation of SMSPCs from an undifferentiated state towards contractile SMCs was Myocd-dependent. Overexpression of Myocd in SMSPCs increased their percentage contraction in response to AngII (P < 0.05) and KCL (P < 0.05) and Ca2+ signalling to levels indistinguishable from rat SMCs. Knockdown of SMC-specific repressors resulted in Myocd-dependent SMC differentiation of SMSPCs. Taking advantage of the fact that SMSPCs possessed unlimited self-renewal capacity ex vivo and could be successfully reprogrammed into functional SMCs, we determined the vascular tissue engineering potential of SMSPCs and showed these cells integrate as viable tissue engineered vascular grafts in vivo. Specifically, after 1 month implantation, a Myocd-GFP+/Isl1+ smooth muscle layer was observed in the grafts along with a vWF+ luminal endothelial layer and multi-layered collagen and elastin fibre formation throughout the graft wall. We have recently isolated cells with similar SMSPC phenotype and differentiation potential from human peripheral blood. This study demonstrates that adult SMSPCs derived from rat BM and human blood can be reprogrammed to efficiently generate large quantities of mature contractile SMCs, displaying great utility as a cellular backbone for tissue engineered vascular grafts, making them an attractive source for vascular cell therapy and surgical applications.

OBJECTIVES: To determine whether the “Checklist for Early Recognition and Treatment of Acute Illness and Injury” decision support tool during ICU admission and rounding is associated with improvements in nonadherence to evidence-based daily care processes and outcomes in variably resourced ICUs. DESIGN, SETTINGS, PATIENTS: This before-after study was performed in 34 ICUs (15 countries) from 2013 to 2017. Data were collected for 3 months before and 6 months after Checklist for Early Recognition and Treatment of Acute Illness and Injury implementation. INTERVENTIONS: Checklist for Early Recognition and Treatment of Acute Illness and Injury implementation using remote simulation training. MEASUREMENTS AND MAIN RESULTS: The coprimary outcomes, modified from the original protocol before data analysis, were nonadherence to 10 basic care processes and ICU and hospital length of stay. There were 1,447 patients in the preimplementation phase and 2,809 patients in the postimplementation phase. After adjusting for center effect, Checklist for Early Recognition and Treatment of Acute Illness and Injury implementation was associated with reduced nonadherence to care processes (adjusted incidence rate ratio [95% CI]): deep vein thrombosis prophylaxis (0.74 [0.68–0.81), peptic ulcer prophylaxis (0.46 [0.38–0.57]), spontaneous breathing trial (0.81 [0.76–0.86]), family conferences (0.86 [0.81–0.92]), and daily assessment for the need of central venous catheters (0.85 [0.81–0.90]), urinary catheters (0.84 [0.80–0.88]), antimicrobials (0.66 [0.62–0.71]), and sedation (0.62 [0.57–0.67]). Analyses adjusted for baseline characteristics showed associations of Checklist for Early Recognition and Treatment of Acute Illness and Injury implementation with decreased ICU length of stay (adjusted ratio of geometric means [95% CI]) 0.86 [0.80–0.92]), hospital length of stay (0.92 [0.85–0.97]), and hospital mortality (adjusted odds ratio [95% CI], 0.81 (0.69–0.95). CONCLUSIONS: A quality-improvement intervention with remote simulation training to implement a decision support tool was associated with decreased nonadherence to daily care processes, shorter length of stay, and decreased mortality.

ABSTRACT Background: The routine use of empiric combination therapy with aminoglycosides during critical illness is associated with uncertain benefit and increased risk of acute kidney injury. This study aimed to assess the benefits of aminoglycosides in immunocompromised patients with suspected bacterial pneumonia and sepsis. Methods: Secondary analysis of a prospective multicenter study. Adult immunocompromised patients with suspected bacterial pneumonia and sepsis or septic shock were included. Primary outcome was hospital mortality. Secondary outcomes were needed for renal replacement therapy (RRT). Mortality was also assessed in neutropenic patients and in those with confirmed bacterial pneumonia. Results were further analyzed in a cohort matched on risk of receiving aminoglycosides combination. Results: Five hundred thirty-five patients were included in this analysis, of whom 187 (35%) received aminoglycosides in addition to another antibiotic effective against gram-negative bacteria. Overall hospital mortality was 59.6% (58.3% vs. 60.3% in patients receiving and not receiving combination therapy; P = 0.71). Lack of association between mortality and aminoglycosides was confirmed after adjustment for confounders and center effect (adjusted OR 1.14 [0.69–1.89]) and in a propensity matched cohort (adjusted OR = 0.89 [0.49–1.61]). No association was found between aminoglycosides and need for RRT (adjusted OR = 0.83 [0.49–1.39], P = 0.477), nor between aminoglycoside use and outcome in neutropenic patients or in patients with confirmed bacterial pneumonia (adjusted OR 0.66 [0.23–1.85] and 1.25 [0.61–2.57], respectively). Conclusion: Aminoglycoside combination therapy was not associated with hospital mortality or need for renal replacement therapy in immunocompromised patients with pulmonary sepsis.