Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsuficiency

Mono-Allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation occurring years later in life, is unclear. This question is unsolved mainly due to lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (tgERG/GATA2het and tgERG/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of ERG/Gata2het fetal liver and bone marrow derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed Oxidative- Phosphorylation related gene-sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AMLs harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, Gata2 deficiency mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for prevention of leukemic transformation in these patients

Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsuficiency.

Mono-Allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation occurring years later in life, is unclear. This question is unsolved mainly due to lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (tgERG/GATA2het and tgERG/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of ERG/Gata2het fetal liver and bone marrow derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed Oxidative- Phosphorylation related gene-sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AMLs harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, Gata2 deficiency mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for prevention of leukemic transformation in these patients

Prospective multicentre study in intensive care units in five cities from the Kingdom of Saudi Arabia: Impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional approach on rates of central line-associated bloodstream infection

OBJECTIVE: To analyse the impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Approach (IMA) and INICC Surveillance Online System (ISOS) on central line-associated bloodstream infection (CLABSI) rates in five intensive care units (ICUs) from October 2013 to September 2015. DESIGN: Prospective, before-after surveillance study of 3769 patients hospitalised in four adult ICUs and one paediatric ICU in five hospitals in five cities. During baseline, we performed outcome and process surveillance of CLABSI applying CDC/NHSN definitions. During intervention, we implemented IMA and ISOS, which included: (1) a bundle of infection prevention practice interventions; (2) education; (3) outcome surveillance; (4) process surveillance; (5) feedback on CLABSI rates and consequences; and (6) performance feedback of process surveillance. Bivariate and multivariate regression analyses were performed. RESULTS: During baseline, 4468 central line (CL) days and 31 CLABSIs were recorded, accounting for 6.9 CLABSIs per 1000 CL-days. During intervention, 12,027 CL-days and 37 CLABSIs were recorded, accounting for 3.1 CLABSIs per 1000 CL-days. The CLABSI rate was reduced by 56% (incidence-density rate, 0.44; 95% confidence interval, 0.28–0.72; P = 0.001). CONCLUSIONS: Implementing IMA through ISOS was associated with a significant reduction in the CLABSI rate in the ICUs of Saudi Arabia

Impact of the International Nosocomial Infection Control Consortium (INICC)’s multidimensional approach on rates of ventilator-associated pneumonia in intensive care units in 22 hospitals of 14 cities of the Kingdom of Saudi Arabia

To analyze the impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Approach (IMA) and use of INICC Surveillance Online System (ISOS) on ventilator-associated pneumonia (VAP) rates in Saudi Arabia from September 2013 to February 2017. A multicenter, prospective, before–after surveillance study on 14,961 patients in 37 intensive care units (ICUs) of 22 hospitals. During baseline, we performed outcome surveillance of VAP applying the definitions of the CDC/NHSN. During intervention, we implemented the IMA and the ISOS, which included: (1) a bundle of infection prevention practice interventions, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback on VAP rates and consequences and (6) performance feedback of process surveillance. Bivariate and multivariate regression analyses were performed using generalized linear mixed models to estimate the effect of intervention. The baseline rate of 7.84 VAPs per 1000 mechanical-ventilator (MV)-days―with 20,927 MV-days and 164 VAPs―, was reduced to 4.74 VAPs per 1000 MV-days―with 118,929 MV-days and 771 VAPs―, accounting for a 39% rate reduction (IDR 0.61; 95% CI 0.5–0.7; P 0.001). Implementing the IMA was associated with significant reductions in VAP rates in ICUs of Saudi Arabia

International Nosocomial Infection Control Consortiu (INICC) report, data summary of 43 countries for 2007-2012. Device-associated module

We report the results of an International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2007-December 2012 in 503 intensive care units (ICUs) in Latin America, Asia, Africa, and Europe. During the 6-year study using the Centers for Disease Control and Prevention's (CDC) U.S. National Healthcare Safety Network (NHSN) definitions for device-associated health care–associated infection (DA-HAI), we collected prospective data from 605,310 patients hospitalized in the INICC's ICUs for an aggregate of 3,338,396 days. Although device utilization in the INICC's ICUs was similar to that reported from ICUs in the U.S. in the CDC's NHSN, rates of device-associated nosocomial infection were higher in the ICUs of the INICC hospitals: the pooled rate of central line–associated bloodstream infection in the INICC's ICUs, 4.9 per 1,000 central line days, is nearly 5-fold higher than the 0.9 per 1,000 central line days reported from comparable U.S. ICUs. The overall rate of ventilator-associated pneumonia was also higher (16.8 vs 1.1 per 1,000 ventilator days) as was the rate of catheter-associated urinary tract infection (5.5 vs 1.3 per 1,000 catheter days). Frequencies of resistance of Pseudomonas isolates to amikacin (42.8% vs 10%) and imipenem (42.4% vs 26.1%) and Klebsiella pneumoniae isolates to ceftazidime (71.2% vs 28.8%) and imipenem (19.6% vs 12.8%) were also higher in the INICC's ICUs compared with the ICUs of the CDC's NHSN