Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.

MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

Methane Carboxylation Using Electrochemically Activated Carbon Dioxide.

Direct synthesis of CH3 COOH from CH4 and CO2 is an appealing approach for the utilization of two potent greenhouse gases that are notoriously difficult to activate. In this Communication, we report an integrated route to enable this reaction. Recognizing the thermodynamic stability of CO2 , our strategy sought to first activate CO2 to produce CO (through electrochemical CO2 reduction) and O2 (through water oxidation), followed by oxidative CH4 carbonylation catalyzed by Rh single atom catalysts supported on zeolite. The net result was CH4 carboxylation with 100 % atom economy. CH3 COOH was obtained at a high selectivity (>80 %) and good yield (ca. 3.2 mmol g-1 cat in 3 h). Isotope labelling experiments confirmed that CH3 COOH is produced through the coupling of CH4 and CO2 . This work represents the first successful integration of CO/O2 production with oxidative carbonylation reaction. The result is expected to inspire more carboxylation reactions utilizing preactivated CO2 that take advantage of both products from the reduction and oxidation processes, thus achieving high atom efficiency in the synthesis.

Implementation of baby boomer hepatitis C screening and linking to care in gastroenterology practices: a multi-center pilot study.

BACKGROUND: Estimates suggest that only 20 % of HCV-infected patients have been identified and <10 % treated. However, baby boomers (1945-1965) are identified as having a higher prevalence of HCV which has led the Centers for Disease Control and Prevention to make screening recommendations. The aim of this study was to implement the CDC's screening recommendations in the unique setting of gastroenterology practices in patients previously unscreened for HCV. METHODS: After obtaining patient informed consent, demographics, clinical and health-related quality of life (HRQOL) data were collected. A blood sample was screened for HCV antibody (HCV AB) using the OraQuick HCV Rapid Antibody Test. HCV AB-positive patients were tested for presence of HCV RNA and, if HCV RNA positive, patients underwent treatment discussions. RESULTS: We screened 2,000 individuals in 5 gastroenterology centers located close to large metropolitan areas on the East Coast (3 Northeast, 1 Mid-Atlantic and 1 Southeast). Of the screened population, 10 individuals (0.5 %) were HCV AB-positive. HCV RNA testing was performed in 90 % (9/10) of HCV AB-positive individuals. Of those, 44.4 % (4/9) were HCV RNA-positive, and all 4 (100 %) were linked to caregiver. Compared to HCV AB negative subjects, HCV AB-positive individuals tended to be black (20.0 vs. 5.2 %, p = 0.09) and reported significantly higher rates of depression: 60.0 vs. 21.5 %, p = 0.009. These individuals also reported a significantly lower HRQOL citing having more fatigue, poorer concentration, and a decreased level of energy (p < 0.05). DISCUSSION: Although the prevalence of HCV AB-positive was low in previously unscreened subjects screened in the gastroenterology centers, the linkage to care was very high. The sample of patients used in this study may be biased, so further studies are needed to assess the effectiveness of the CDC screening recommendations. CONCLUSION: Implementation of the Baby Boomer Screening for HCV requires identifying screening environement with high prevalence of HCV+ individuals as well as an efficient process of linking them to care.

No diversion in Western Massachusetts.

BACKGROUND: Massachusetts (MA) instituted a moratorium on ambulance diversion ("No Diversion") on January 1, 2009. STUDY OBJECTIVES: Determine whether No Diversion was associated with changes in Emergency Department (ED) throughput measures. DESIGN: Comparison of three 3-month periods. Period 1: 1 year prior (January-March 2008); Period 2: 3 months prior (October-December 2008); Period 3: 3 months after (January-March 2009). SETTING: Seven EDs in Western MA; two - including the only Level I Trauma Center - were "high" diversion (≥562 h/year) and 5 were "low" diversion (≤260 h/year). For "all," "high" diversion and "low" diversion ED groups, we compared mean monthly throughput measures, including: 1) total volume, 2) number of admissions, 3) number of elopements, 4) length of stay for all, admitted and discharged patients. Mean absolute and percent changes were estimated using mixed-effects regression analysis. Linear mixed models were run for "all," "high" and "low" diversion EDs comparing means of changes between periods. Results are presented as mean change per month in number and percent, and 95% confidence intervals were calculated. We specified that a clinically significant effect of No Diversion had to meet two criteria: 1) there was a consistent difference in the means for both the Period 1 vs. Period 3 comparison and the Period 2 vs. Period 3 comparison, and 2) both comparisons had to achieve statistical significance at p ≤ 0.01. RESULTS: According to pre-determined criteria, no clinically significant changes were found in any ED group in mean monthly volume, admissions, elopements, or length-of-stay for any patient disposition group. CONCLUSION: No Diversion was not associated with significant changes in throughput measures in "all," "high" diversion and "low" diversion EDs.

Emergency department patients who stay more than 6 hours contribute to crowding.

BACKGROUND: Admitted and discharged patients with prolonged emergency department (ED) stays may contribute to crowding by utilizing beds and staff time that would otherwise be used for new patients. OBJECTIVES: To describe patients who stay > 6 h in the ED and determine their association with measures of crowding. METHODS: This was a retrospective, observational study carried out over 1 year at a single, urban, academic ED. RESULTS: Of the 96,562 patients seen, 16,017 (17%) stayed > 6 h (51% admitted). When there was at least one patient staying > 6 h, 60% of the time there was at least one additional patient in the waiting room who could not be placed in an ED bed because none was open. The walk-out rate was 0.34 patients/hour when there were no patients staying in the ED > 6 h, vs. 0.77 patients/hour walking out when there were patients staying > 6 h in the ED (p < 0.001). When the ED contained more than 3 patients staying > 6 h, a trend was noted between increasing numbers of patients staying in the ED > 6 h and the percentage of time the ED was on ambulance diversion (p = 0.011). CONCLUSION: In our ED, having both admitted and discharged patients staying > 6 h is associated with crowding.

Process modification and emergency department radiology service.

Our purpose was to demonstrate the impact of changes in technology, staffing, and departmental processes on service levels in emergency department (ED) radiology. We also attempted to determine if report turnaround time affects ED patient throughput. Radiology performance was evaluated before and after the modifications of processes integral to the interpretation of ED imaging. Picture archiving and communication system, voice recognition (VR), staffing, physical site, work flow, and administrative modifications were undertaken over approximately 2 years. The average time interval from the exam completion to report signature was 5,184 min (standard deviation (SD) of 1,858 min before the implementation of VR and other modifications of ED radiology processes). In post initial modifications, it was 150 min (SD, 169 min) and 157 min (SD, 215 min) in post additional modifications. The percentage of the signed written reports available in less than or equal to 60 min was 0%, 27%, and 40%, respectively. Ongoing improvements are needed to increase the service levels for ED radiology. Further improvement will require collaboration and adjustment with the ongoing assessment of metrics.

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.

UNLABELLED: This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. CONCLUSION: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Antiviral response of HCV genotype 1 to consensus interferon and ribavirin versus pegylated interferon and ribavirin.

Achieving an antiviral response at a reasonable cost is a challenge in the treatment of patients with chronic hepatitis C. A previous study indicated that consensus interferon with ribavirin had promising activity against hepatitis C virus (HCV) genotype 1. The objective of this study was to determine the virologic response with consensus interferon or pegylated interferon alpha-2b plus weight-ribavirin in patients chronically infected with HCV genotype 1. Intention-to-treat analysis showed response in 37% and 41% of subjects treated with consensus interferon/ribavirin or pegylated interferon/ribavirin, respectively, with response rates of 42% and 44% observed in analysis of the per-protocol population, not a significant difference. Tolerability of the two treatment regimens was similar. In conclusion, both treatment regimens were safe and gave a similar antiviral response. It is possible that if consensus interferon is administered daily rather than three times weekly, eradication of HCV could be achieved in a larger proportion of patients infected with HCV genotype 1.

A descriptive study of heavy emergency department users at an academic emergency department reveals heavy ED users have better access to care than average users.

INTRODUCTION: Emergency department (ED) overcrowding has been a significant problem for the last 10 years. Several studies have shown that a relatively small number of ED patients are responsible for a disproportionate amount of ED visits. This study aims to describe the frequent users of our emergency department. METHODS: This was an institutional review board-approved descriptive study performed by a retrospective review of electronic records. This pilot describes and compares patients who had 12 or more ED visits during the study year with those who visited less. RESULTS: The 234 patients who met criteria for high-frequency use (HFU) of the emergency department were responsible for a total of 4633 visits. Sex, race, and age distribution of HFU patients were similar to those of general ED patients. Eighty-four percent of HF users have insurance and 93% have primary care providers. A relatively small percentage of HFU visits, 4%, were mental health-related visits and 3% were alcohol- and drug-related visits. The HFU visits are socially connected: 93% have their own homes; 94% have relatives or friends; 73% have a religious affiliation. Pain or pain-related conditions are the most common diagnoses. These patients are also frequent users of ambulatory care services. CONCLUSION: The similarities between our HFU and the general ED population are more numerous than their differences. The HFU patients of our emergency department are different in terms of age, employment status, and type of insurance. IMPLICATIONS FOR NURSES: A detailed description of local HFU may help to inform planning and better meet ED patients' needs. As one of many results of this study, the ED chairman met with the Hematology-Oncology team and reviewed the protocol for ED management of sickle cell crisis. The meeting resulted in a revised protocol, including an immediate change in their pain medication from meperidine to either morphine or hydromorphone.