Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model [v1; ref status: approved with reservations 1, http://f1000r.es/5l9]

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development

Energy fluxes in helical magnetohydrodynamics and dynamo action

Renormalized viscosity, renormalized resistivity, and various energy fluxes are calculated for helical magnetohydrodynamics using perturbative field theory. The calculation is to first-order in perturbation. Kinetic and magnetic helicities do not affect the renormalized parameters, but they induce an inverse cascade of magnetic energy. The sources for the the large-scale magnetic field have been shown to be (1) energy flux from large-scale velocity field to large-scale magnetic field arising due to nonhelical interactions, and (2) inverse energy flux of magnetic energy caused by helical interactions. Based on our flux results, a premitive model for galactic dynamo has been constructed. Our calculations yields dynamo time-scale for a typical galaxy to be of the order of $10^8$ years. Our field-theoretic calculations also reveal that the flux of magnetic helicity is backward, consistent with the earlier observations based on absolute equilibrium theory.Comment: REVTEX4; A factor of 2 corrected in helicit

Reducing Rehospitalizations through Automated Alerts to Primary Care Providers and Staff When Older Patients are Discharged from the Hospital: A Randomized Trial

Background: Inadequate continuity of care places older patients at very high risk during transitions from the hospital to ambulatory setting. Methods: We conducted a randomized controlled trial of an HIT-based transitional care intervention in patients aged 65 and older discharged from hospital to home. All patients were senior plan members of a Massachusetts-based health plan, and cared for by a multispecialty medical group using the EpicCare Ambulatory Medical Record. In addition to notifying providers about the patient’s recent transition, the system provided information about new drugs added during the inpatient stay, warnings about drug-drug interactions, recommendations for dose changes and laboratory monitoring of high-risk medications, and reminded the primary care provider’s support staff to schedule a post-hospitalization office visit. Randomization occurred at the time of hospital discharge during a one-year intervention period beginning in August 2010. Alerts were automatically delivered to the provider and staff in-basket within the EMR. The primary outcomes were: 1) having an outpatient office visit with the primary care provider within 30 days following discharge; and 2) having a rehospitalization within 30 days following discharge. Results: The study included 3667 discharges of which 1877 discharges were randomly assigned to the intervention arm. Forty-nine percent of discharges in the intervention arm were followed by office visits with the primary care provider within 30 days, compared to 51% in the comparison arm (RR 0.96, 95% CI 0.90, 1.03). Eighteen percent of discharges in the intervention arm were followed by a rehospitalization within 30 days compared to 20% in the comparison arm (RR 0.92, 95% CI 0.80, 1.05). Conclusions: This HIT-based intervention was not effective in increasing the percentage of hospital discharges of older patients that were followed by timely office visits to primary care providers or reducing the percentage with rehospitalization

Adverse Drug Events Post-Hospital Discharge in Older Patients: Types, Severity, and Involvement of Beers Criteria Medications

Objective: To characterize adverse drug events (ADEs) occurring within the high-risk 45-day period post-hospitalization in older adults. Design: Clinical pharmacists reviewed the ambulatory records of 1000 consecutive discharges. Setting: A large multispecialty group practice closely aligned with a Massachusetts-based health plan. Participants: Hospitalized patients aged 65 years and older who were discharged to home. Measurements: Possible drug-related incidents occurring during the 45-day period post-hospitalization were identified and presented to a pair of physician-reviewers who classified incidents as to whether an ADE was present, whether the event was preventable, and the severity of the event. Medications implicated in ADEs were further characterized according to their inclusion in the 2012 Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Results: At least one ADE was identified during the 45-day period in 18.7% (187) of the 1000 discharges. Of the 242 ADEs identified, 35% (n=84) were deemed preventable, of which 32% (n=27) were characterized as serious, and 5% (n=4) as life threatening. Over half of all ADEs occurred within the first 14 days post-hospitalization. The percentage of ADEs in which Beers Criteria medications were implicated was 16.5% (n=40). Beers Criteria medications with both a high quality of evidence and strong strength of recommendation were implicated in 6.6% (n=16) of the ADEs. Conclusion: ADEs are common and often preventable among older adults following hospital discharge, underscoring the need to address medication safety during this high-risk period in this vulnerable population. Beers Criteria medications played a small role in these events suggesting that efforts to improve the quality and safety of medication use during this critical transition period must extend beyond a singular focus on Beers criteria medications

DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and ‘hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma

Search for New Physics with Jets and Missing Transverse Momentum in pp collisions at sqrt(s) = 7 TeV

A search for new physics is presented based on an event signature of at least three jets accompanied by large missing transverse momentum, using a data sample corresponding to an integrated luminosity of 36 inverse picobarns collected in proton--proton collisions at sqrt(s)=7 TeV with the CMS detector at the LHC. No excess of events is observed above the expected standard model backgrounds, which are all estimated from the data. Exclusion limits are presented for the constrained minimal supersymmetric extension of the standard model. Cross section limits are also presented using simplified models with new particles decaying to an undetected particle and one or two jets

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

Search for anomalous t t-bar production in the highly-boosted all-hadronic final state

A search is presented for a massive particle, generically referred to as a Z', decaying into a t t-bar pair. The search focuses on Z' resonances that are sufficiently massive to produce highly Lorentz-boosted top quarks, which yield collimated decay products that are partially or fully merged into single jets. The analysis uses new methods to analyze jet substructure, providing suppression of the non-top multijet backgrounds. The analysis is based on a data sample of proton-proton collisions at a center-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 5 inverse femtobarns. Upper limits in the range of 1 pb are set on the product of the production cross section and branching fraction for a topcolor Z' modeled for several widths, as well as for a Randall--Sundrum Kaluza--Klein gluon. In addition, the results constrain any enhancement in t t-bar production beyond expectations of the standard model for t t-bar invariant masses larger than 1 TeV.Comment: Submitted to the Journal of High Energy Physics; this version includes a minor typo correction that will be submitted as an erratu

Measurement of the t t-bar production cross section in the dilepton channel in pp collisions at sqrt(s) = 7 TeV

The t t-bar production cross section (sigma[t t-bar]) is measured in proton-proton collisions at sqrt(s) = 7 TeV in data collected by the CMS experiment, corresponding to an integrated luminosity of 2.3 inverse femtobarns. The measurement is performed in events with two leptons (electrons or muons) in the final state, at least two jets identified as jets originating from b quarks, and the presence of an imbalance in transverse momentum. The measured value of sigma[t t-bar] for a top-quark mass of 172.5 GeV is 161.9 +/- 2.5 (stat.) +5.1/-5.0 (syst.) +/- 3.6(lumi.) pb, consistent with the prediction of the standard model.Comment: Replaced with published version. Included journal reference and DO