Practical Strategies Related to the Application of Balloon Tamponade Therapy in Acute Variceal Bleeding.

IMPORTANCE: Acute gastrointestinal variceal hemorrhage is a major cause of morbidity and mortality in cirrhotic liver disease. Approximately one-third of cirrhotic patients will have variceal hemorrhage, and each bleeding episode is associated with up to 20% mortality. Balloon tamponade devices are used to achieve temporary hemostasis of bleeding esophagogastric varices and as a bridge to definitive therapy. Rapid and proper placement is crucial in a life-threatening bleed both to improve patient's chances of survival and minimize procedural complications. Passage of the tube can be complicated by coiling in the oropharynx or mid-esophagus particularly if an endotracheal tube is in place or the patient has large variceal burden. Endoscopic placement can be a useful adjunct but may not be readily accessible depending on resources and availability of specialists. Here, we describe a technique of balloon tamponade placement using a stiffening guidewire to overcome this challenge. OBJECTIVES: The objectives were to: 1) describe the guidewire method for balloon tamponade tube placement and 2) highlight proof of concept through clinical application. DESIGN: We conducted a retrospective case series of patients treated with balloon tamponade using the guidewire method. SETTING AND PARTICIPANTS: This study was done at a single-center quaternary-care facility. Patients admitted to the surgical ICU and treated with a balloon tamponade device for acute variceal hemorrhage were included. MAIN OUTCOMES AND MEASURES: Patient characteristics were assessed including age, sex, model for end stage liver disease score, etiology of cirrhosis, and definitive treatment received. RESULTS: Nine patients were included in the final analysis. Mean age was 50 ± 19, and mean model for end stage liver disease was 39 ± 8. Alcohol cirrhosis was the most common cause of cirrhosis in this sample (n = 5). Six patients were able to be bridged to definitive treatment. CONCLUSIONS AND RELEVANCE: Guidewire-assisted balloon tamponade placement is practical, is effective, and can be performed by acute care providers.

Factors Associated With Mortality Among Patients Managed for Large Volume Hemorrhage in a Medical Intensive Care Unit.

PURPOSE: Our goal was to describe resuscitation practices in critically ill medical patients with active hemorrhage requiring large volume resuscitation and identify factors associated with poor outcomes. PATIENTS AND METHODS: This was a single center retrospective observational cohort study. Patients admitted to the medical intensive care unit from 2011 to 2017 who received ≥5 units of packed red blood cells (pRBCs) within 24 h were included. Data including volume of blood products and crystalloid administered, baseline sequential organ failure assessment (SOFA) scores, and outcomes were abstracted. Univariate and multivariate analyses were performed to determine clinical factors associated with hospital mortality. RESULTS: Two hundred forty-six patients were identified. Mean volumes of 2,448 mL of pRBCs and 3.9L of crystalloid were transfused over 24 h. Inpatient mortality for the entire cohort was 48%. Multivariable analysis identified factors associated with hospital mortality; higher BMI (OR 1.047, 95% CI 1.013-1.083), higher ratio of fresh frozen plasma (FFP) to pRBCs (OR 2.744, 95% CI 1.1-6.844), and higher baseline SOFA scores (OR 1.3, 95% CI 1.175-1.437). CONCLUSION: In a cohort of critically ill medical patients undergoing resuscitation for hemorrhage, higher BMI, increased ratio of FFP to pRBCs, and higher SOFA scores were associated with increased mortality. Further studies are needed to clarify resuscitation practices associated with outcomes in this population.

ETV6-NCOA2 fusion induces T/myeloid mixed-phenotype leukemia through transformation of nonthymic hematopoietic progenitor cells.

Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation that creates the ETV6-NCOA2 fusion with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1-activating mutations. Similarly, cotransduction of human cord blood CD34+ progenitors with ETV6-NCOA2 and a nontransforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern were similar to those of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse nonthymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at an early immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.

Compressive epidural fluid collection secondary to varicella zoster transverse myelitis.

Transverse myelitis is often clinically indistinguishable from compressive myelopathies that require emergent neurosurgical intervention. Here, we present a case of acute varicella zoster virus transverse myelitis that was associated with a compressive fluid collection on magnetic resonance imaging (MRI) requiring emergent operative intervention. To our knowledge, this is the first reported case of acute transverse myelitis and a compressive cord lesion in the adult population.

Structure-function analysis of MurJ reveals a solvent-exposed cavity containing residues essential for peptidoglycan biogenesis in Escherichia coli.

Gram-negative bacteria such as Escherichia coli build a peptidoglycan (PG) cell wall in their periplasm using the precursor known as lipid II. Lipid II is a large amphipathic molecule composed of undecaprenyl diphosphate and a disaccharide-pentapeptide that PG-synthesizing enzymes use to build the PG sacculus. During PG biosynthesis, lipid II is synthesized at the cytoplasmic face of the inner membrane and then flipped across the membrane. This translocation of lipid II must be assisted by flippases thought to shield the disaccharide-pentapeptide as it crosses the hydrophobic core of the membrane. The inner membrane protein MurJ is essential for PG biogenesis and homologous to known and putative flippases of the MOP (multidrug/oligo-saccharidyl-lipid/polysaccharide) exporter superfamily, which includes flippases that translocate undecaprenyl diphosphate-linked oligosaccharides across the cytoplasmic membranes of bacteria. Consequently, MurJ has been proposed to function as the lipid II flippase in E. coli. Here, we present a three-dimensional structural model of MurJ generated by the I-TASSER server that suggests that MurJ contains a solvent-exposed cavity within the plane of the membrane. Using in vivo topological studies, we demonstrate that MurJ has 14 transmembrane domains and validate features of the MurJ structural model, including the presence of a solvent-exposed cavity within its transmembrane region. Furthermore, we present functional studies demonstrating that specific charged residues localized in the central cavity are essential for function. Together, our studies support the structural homology of MurJ to MOP exporter proteins, suggesting that MurJ might function as an essential transporter in PG biosynthesis.