Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML

Mirizzi syndrome type IV associated with cholecystocolic fistula: a very rare condition- report of a case

<p>Abstract</p> <p>Background</p> <p>Mirizzi syndrome is a rare complication of prolonged cholelithiasis with presence of large, impacted gallstone into the Hartman's pouch, causing chronic extrinsic compression of common bile duct (CBD). Fistula formation between the CBD and the gallbladder may represent an outcome of that condition. According to Mirizzi's classification and Csendes's subclassification, Mirizzi syndrome type IV represents the most uncommon type (4%).</p> <p>Spontaneous biliary-enteric fistulas have also been rarely reported (1.2–5%) in a large series of cholecystectomies. Cholecystocolic fistula is the most infrequent biliary enteric fistula, causing significant morbidity and representing a diagnostic challenge.</p> <p>Case presentation</p> <p>We describe a very rare, to our knowledge, combination of Mirizzi syndrome type IV and cholecystocolic fistula. A 52 year old male, presented to our clinic complaining of episodic diarrhea (monthly episodes lasting 16 days), high temperature (38°C–39°C), right upper quadrant pain without jaundice. The definitive diagnosis was made intraoperatively. Magnetic Resonance Imaging (MRI) and Endoscopic Retrograde Cholangiopancreatography (ERCP) demonstrated the presence of Mirizzi syndrome with cholecystocolic fistula formation. The patient was operated upon, and cholecystectomy, cholecystocolic fistula excision and Roux-en-Y biliary-enteric anastomosis were undertaken with excellent post-operative course.</p> <p>Conclusion</p> <p>Appropriate biliary tree imaging with ERCP and MRI/MRCP is essential for the diagnosis of Mirizzi syndrome and its complications. Cholecystectomy, fistula excision and biliary-enteric anastomosis with Roux-en-Y loop appears to be the most appropriate surgical intervention in order to avoid damage to Calot's triangle anatomic elements. Particularly in our case, ERCP was a valuable diagnostic tool that Mirizzi syndrome type IV and cholecystocolic fistula.</p

From staff-mix to skill-mix and beyond: towards a systemic approach to health workforce management

Throughout the world, countries are experiencing shortages of health care workers. Policy-makers and system managers have developed a range of methods and initiatives to optimise the available workforce and achieve the right number and mix of personnel needed to provide high-quality care. Our literature review found that such initiatives often focus more on staff types than on staff members' skills and the effective use of those skills. Our review describes evidence about the benefits and pitfalls of current approaches to human resources optimisation in health care. We conclude that in order to use human resources most effectively, health care organisations must consider a more systemic approach - one that accounts for factors beyond narrowly defined human resources management practices and includes organisational and institutional conditions

An adapted Clavien-Dindo scoring system in trauma as a clinically meaningful non-mortality endpoint

BACKGROUND: There is no consensus on reporting nonmortality trauma complications in a graded manner. The Clavien-Dindo scale of complications was originally for elective surgery and requires adaptation to provide meaningful data for trauma patients. In particular, the original score does not account for those treated without surgery. We report an adapted Clavien-Dindo in trauma (ACDiT) scale and apply it to patients managed operatively and nonoperatively. METHODS: A combined prospective and retrospective international multicenter observational study was undertaken to apply the ACDiT scale to 484 trauma patients at three university teaching hospitals (Birmingham, England (n = 303); Houston, Texas (n = 113); and Glasgow, Scotland (n = 68)). These included both intensive care unit (ICU) and non-ICU-managed patients. The Clavien-Dindo scoring system was adapted for trauma patients based on consensus amongst an international collaboration of trauma specialists at these sites. Data included whether initial patients were managed operatively or nonoperatively. Complication grades were compared with hospital-free and ICU-free days as other outcome measures of patient morbidity. RESULTS: Two hundred seventeen (44.8%) of 484 patients experienced complications, of whom 61 (28.1%) of 217 died (grade V). The remainder consisted of grades I (n = 20), II (n = 60), III (n = 24), and IV (n = 52). There was a strong association between higher ACDiT grade category and lower number of hospital-free and ICU-free days (p < 0.01). Eighty-eight patients with complications did not require surgery, validating the score's usefulness in patients managed nonoperatively. CONCLUSION: The ACDiT scale can be used to grade the severity of posttrauma complications in patients managed both operatively and nonoperatively. It provides clinically meaningful data for morbidity and mortality meetings and other quality improvement exercises. LEVEL OF EVIDENCE: Prognostic, level IV