bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revisiting the Gram-Negative Lipoprotein Paradigm
Authors: LoVullo Eric D. , Wright Lori F. , Isabella Vincent , Huntley Jason F. , Pavelka Martin S. 
Published: March 2015

ABSTRACT

The processing of lipoproteins (Lpps) in Gram-negative bacteria is generally considered an essential pathway. Mature lipoproteins in these bacteria are triacylated, with the final fatty acid addition performed by Lnt, an apolipoprotein N-acyltransferase. The mature lipoproteins are then sorted by the Lol system, with most Lpps inserted into the outer membrane (OM). We demonstrate here that the
lnt
gene is not essential to the Gram-negative pathogen
Francisella tularensis
subsp.
tularensis
strain Schu or to the live vaccine strain LVS. An LVS Δ
lnt
mutant has a small-colony phenotype on sucrose medium and increased susceptibility to globomycin and rifampin. We provide data indicating that the OM lipoprotein Tul4A (LpnA) is diacylated but that it, and its paralog Tul4B (LpnB), still sort to the OM in the Δ
lnt
mutant. We present a model in which the Lol sorting pathway of
Francisella
has a modified ABC transporter system that is capable of recognizing and sorting both triacylated and diacylated lipoproteins, and we show that this modified system is present in many other Gram-negative bacteria. We examined this model using
Neisseria gonorrhoeae
, which has the same Lol architecture as that of
Francisella
, and found that the
lnt
gene is not essential in this organism. This work suggests that Gram-negative bacteria fall into two groups, one in which full lipoprotein processing is essential and one in which the final acylation step is not essential, potentially due to the ability of the Lol sorting pathway in these bacteria to sort immature apolipoproteins to the OM.

IMPORTANCE
This paper describes the novel finding that the final stage in lipoprotein processing (normally considered an essential process) is not required by
Francisella tularensis
or
Neisseria gonorrhoeae
. The paper provides a potential reason for this and shows that it may be widespread in other Gram-negative bacteria.
Anonymisation of address coordinates for microlevel analyses of the built environment: a simulation study
Authors: Buck Christoph , Dreger Steffen , Pigeot Iris 
Published: March 2015

BackgroundData privacy is a major concern in spatial epidemiology because exact residential locations or parts of participants’ addresses such as street or zip codes are used to perform geospatial analyses. To overcome this concern, different levels of aggregation such as census districts or zip code areas are mainly used, though any spatial aggregation leads to a loss of spatial variability. For the assessment of urban opportunities for physical activity that was conducted in the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study, macrolevel analyses were performed, but the use of exact residential addresses for micro-level analyses was not permitted by the responsible office for data protection. We therefore implemented a spatial blurring to anonymise address coordinates depending on the underlying population density.MethodsWe added a standard Gaussian distributed error to individual address coordinates with the variancedepending on the population density and on the chosen k-anonymity. 1000 random point locations were generated and repeatedly blurred 100 times to obtain anonymised locations. For each location 1 km network-dependent neighbourhoods were used to calculate walkability indices. Indices of blurred locations were compared to indices based on their sampling origins to determine the effect of spatial blurring on the assessment of the built environment.ResultsSpatial blurring decreased with increasing population density. Similarly, mean differences in walkability indices also decreased with increasing population density. In particular for densely-populated areas with at least 1500 residents per km², differences between blurred locations and their sampling origins were small and did not affect the assessment of the built environment after spatial blurring.ConclusionsThis approach allowed the investigation of the built environment at a microlevel using individual network-dependent neighbourhoods, while ensuring data protection requirements. Minor influence of spatial blurring on the assessment of walkability was found that slightly affected the assessment of the built environment in sparsely-populated areas.
Regorafenib assessment in refractory advanced colorectal cancer: RegARd-C study protocol
Authors: Hendlisz Alain , Deleporte Amélie , Vandeputte Caroline , Charette Nicolas , Paesmans Marianne , Guiot Thomas , Garcia Camilo , Flamen Patrick 
Published: March 2015

IntroductionRegorafenib was recently approved for patients with pretreated advanced colorectal cancer (aCRC), despite a moderate improvement of the patients’ outcome, and significant toxicities. Based on previous studies showing that early fluorodeoxyglucose-positron emission tomography (FDG-PET)-based metabolic response assessment (MRA) might adequately select patients unlikely to benefit from treatment, the RegARd-C trial uses early MRA to identify likely non-responders to regorafenib in a population of patients with aCRC and guide a comprehensive evaluation of genomic and epigenetic determinants of resistance to treatment.Methods and analysisRegARd-C is a multicentric prospective study. Its primary objective is to identify non-benefitters from regorafenib given at 160 mg/day, 3 weeks out of 4 in a population of patients with pretreated aCRC. Baseline PET is repeated at day 14 of the first treatment course. MRA is blinded for the investigators. Overall survival (OS) is the primary end point and will be correlated with metabolic parameters and (epi)genetic alterations assessed from tumour and serial blood samples. A target sample size of 105 evaluable patients (70 as derivation set and 35 as validation set), is considered as sufficient to validate an expected HR for OS of metabolic responders compared to metabolic non-responders significantly <1 (with 80% power and 1-sided 5% α in case of a true HR≤0.59 and a responders rate of 47%).Ethics and disseminationThe study was approved by the Institut Jules Bordet's competent ethics committee and complies with the Helsinki declaration or the Belgian laws and regulations, whichever provides the greatest protection for the patient, and follows the International Conference on Harmonisation E 6 (R1) Guideline for Good Clinical Practice, reference number CPMP/ICH/135/95. The protocol and the trials results, even inconclusive, will be presented at international oncology congresses, and published in peer-reviewed journals. Genomic and epigenetic data will be made available in public open data sets.Trial registration numbersEudraCT number: 2012-005655-16; ClinicalTrials.gov number:NCT01929616.
Reducing stress and burnout in junior doctors: the impact of debriefing sessions
Authors: Gunasingam Nishmi , Burns Kharis , Edwards James , Dinh Michael , Walton Merrilyn 
Published: March 2015

ABSTRACT

Background
Internship and residency are difficult times with novice practitioners facing new challenges and stressors. Junior doctors may experience burnout, a syndrome that encompasses three dimensions: emotional exhaustion, depersonalisation and reduced personal accomplishment. While there is some existing literature on the prevalence of burnout in junior doctors, there are few studies on interventional strategies.

Aims
This study aimed to examine the prevalence of burnout in a cohort of junior doctors and whether debriefing sessions reduced levels of burnout.

Methods
A prospective randomised controlled study of a convenience sample of postgraduate year 1 doctors in a single hospital was undertaken during a rotation term in 2011. All participants completed a questionnaire using a validated tool, the Maslach Burnout Inventory, to determine the prevalence of burnout. They were then randomly assigned to a group who were to receive four debriefing sessions over 2 months, or, to the control group, who had no debriefing sessions. Quantitative and qualitative analyses were conducted.

Results
Thirty-one postgraduate year 1 doctors participated in the study, with 13 being assigned to the group receiving debriefing sessions and 18 assigned to the control group. At baseline, 21/31 (68%) participants displayed evidence of burnout in at least one domain as measured by the Maslach Burnout Inventory. Burnout was significantly higher in women. There was no significant difference in burnout scores with debriefing. The intervention was well received with 11/18 (61%) suggesting they would recommend the strategy to future junior doctors and 16/18 (89%) found that the sessions were a source of emotional and social support.

Conclusions
Burnout is prevalent among postgraduate year 1 doctors, and they value the emotional and social support from attending debriefing sessions. A larger study is required to determine if debriefing can reduce the incidence of burnout in junior doctors.
Elucidation of Acquired Resistance to Bcl-2 and MDM2 Inhibitors in Acute Leukemia In Vitro and In Vivo
Authors: Hoffman-Luca C. Gianna , Ziazadeh Daniel , McEachern Donna , Zhao Yujun , Sun Wei , Debussche Laurent , Wang Shaomeng 
Published: March 2015

Abstract
Purpose: Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance. Elucidation of acquired resistance mechanisms and development of strategies to overcome the resistance are critical for their successful clinical development.
Experimental Design: We employed RS4;11 and MV4;11 cell lines, two acute leukemia models, to investigate acquired resistance mechanisms for both drugs in vitro and in vivo and evaluated several treatment regimens in xenograft mouse models to improve long-term, complete tumor regression.
Results: Resistance to either SAR405838 or ABT-263 (or its analogue ABT-737) develops in acute leukemia models in vitro and in vivo. RS4;11 and MV4;11 tumors treated with SAR405838 acquire resistance to the drug by mutation of the TP53 gene or compromise of p53 protein function. RS4;11 tumors treated with either ABT-263 or ABT-737 acquire resistance primarily through downregulation of BAX but not BAK. When acute leukemia cells become highly resistant to the MDM2 inhibitor, they retain their sensitivity to the Bcl-2 inhibitors, or vice versa. Certain sequential or combination treatment of SAR405838 and ABT-263 can achieve longer-term tumor regression than treatment with either agent alone.
Conclusions: Our study provides new insights into the mechanisms of acquired resistance of Bcl-2 and MDM2 inhibitors in acute leukemia models and suggests that certain sequential or combination treatment of these two distinct classes of apoptosis-inducing agents should be tested as new treatment strategies for acute leukemia in the clinic. Clin Cancer Res; 21(11); 2558–68. ©2015 AACR.
Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice?
Authors: Paiva Bruno , Puig Noemi , García-Sanz Ramón , San Miguel Jesús F. 
Published: March 2015

Abstract
Increasing therapeutic options and prolonged survival in multiple myeloma have raised interest in the concept of depth of response and its importance to predict patients' outcomes. Although the efficacy of current treatment approaches has greatly improved in the past decade, the definition of complete response (CR) remains unaltered and continues to use conventional serological and morphologic techniques. That notwithstanding, there is growing interest in minimal residual disease (MRD) monitoring, which has emerged in recent years as one of the most relevant prognostic factors in multiple myeloma. MRD can be assessed both inside (e.g., immunophenotypic and molecular techniques) and outside the bone marrow (e.g., PET/CT). Here, we focus on flow- and molecular-based assays by which different cooperative groups have demonstrated the efficacy of MRD assessment to predict outcomes even among patients in CR, and irrespectively of disease risk. Although further standardization is still required, the time has come to implement MRD monitoring in prospective clinical trials as a sensitive tool to evaluate treatment efficacy and for risk-adapted treatment, particularly in the consolidation and maintenance settings. Here, we present a comprehensive and critical review on the methodologic aspects, specific characteristics, and clinical significance of MRD monitoring by flow cytometry, PCR, and next-generation sequencing. Clin Cancer Res; 21(9); 2001–8. ©2015 AACR.
Early Resting Myocardial Computed Tomography Perfusion for the Detection of Acute Coronary Syndrome in Patients With Coronary Artery Disease
Authors: Pursnani Amit , Lee Ashley M. , Mayrhofer Thomas , Ahmed Waleed , Uthamalingam Shanmugam , Ferencik Maros , Puchner Stefan B. , Bamberg Fabian , Schlett Christopher L. , Udelson James , Hoffmann Udo , Ghoshhajra Brian B. 
Published: March 2015

Background—
Acute rest single-photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) has high predictive value for acute coronary syndrome (ACS) in emergency department patients. Prior studies have shown excellent agreement between rest/stress computed tomography perfusion (CTP) and SPECT-MPI, but the value of resting CTP (rCTP) in acute chest pain triage remains unclear. We sought to determine the diagnostic accuracy of early rCTP, incremental value beyond obstructive coronary artery disease (CAD; ≥50% stenosis), and compared early rCTP to late stress SPECT-MPI in patients with CAD presenting with suspicion of ACS to the emergency department.

Methods and Results—

In this prespecified subanalysis of 183 patients (58.1±10.2 years; 33% women), we included patients with any CAD by coronary computed tomography angiography (CCTA) from Rule Out Myocardial Infarction Using Computer-Assisted Tomography I. rCTP was assessed semiquantitatively, blinded to CAD interpretation. Overall, 31 had ACS and 48 had abnormal rCTP. Sensitivity and specificity of rCTP for ACS were 48% (95% confidence interval [CI], 30%–67%) and 78% (95% CI, 71%–85%), respectively. rCTP predicted ACS (adjusted odds ratio, 3.40 [95% CI, 1.37–8.42];
P
=0.008) independently of obstructive CAD, and sensitivity for ACS increased from 77% (95% CI, 59%–90%) for obstructive CAD to 90% (95% CI, 74%–98%) with addition of rCTP (
P
=0.05). In a subgroup undergoing late rest/stress SPECT-MPI (n=81), CCTA/rCTP had noninferior discriminatory value to CCTA/SPECT-MPI (area under the curve, 0.88 versus 0.90;
P
=0.64) using a noninferiority margin of 10%.

Conclusions—
Early rCTP provides incremental value beyond obstructive CAD to detect ACS. CCTA/rCTP is noninferior to CCTA/SPECT-MPI to discriminate ACS and presents an attractive alternative to triage patients presenting with acute chest pain.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00990262.
Estimating Snow Cover Duration from Ground Temperature
Authors: Teubner Irene E. , Haimberger Leopold , Hantel Michael 
Published: March 2015

AbstractSnow cover duration is commonly derived from snow depth, snow water equivalent, or satellite data. Snow cover duration has more recently also been inferred from ground temperature data. In this study, a probabilistic snow cover duration (SCD) model is introduced that estimates the conditional probability for snow cover given the daily mean and the diurnal range of ground temperature. For the application of the SCD model, 87 Austrian sites in the Alpine region are investigated in the period of 2000 to 2011. The daily range of ground temperature is identified to represent the primary variable in determining the snow cover duration. In the case of a large dataset, however, the inclusion of the daily mean ground temperature as the second given parameter improves results. Rank correlation coefficients of predicted versus observed snow cover duration are typically between 0.8 and 0.9.
Multidecadal Variability of Tropical Cyclone Rapid Intensification in the Western North Pacific
Authors: Wang Xidong , Wang Chunzai , Zhang Liping , Wang Xin 
Published: March 2015

Abstract
This study investigates the variation of tropical cyclone (TC) rapid intensification (RI) in the western North Pacific (WNP) and its relationship with large-scale climate variability. RI events have exhibited strikingly multidecadal variability. During the warm (cold) phase of the Pacific decadal oscillation (PDO), the annual RI number is generally lower (higher) and the average location of RI occurrence tends to shift southeastward (northwestward). The multidecadal variations of RI are associated with the variations of large-scale ocean and atmosphere variables such as sea surface temperature (SST), tropical cyclone heat potential (TCHP), relative humidity (RHUM), and vertical wind shear (VWS). It is shown that their variations on multidecadal time scales depend on the evolution of the PDO phase. The easterly trade wind is strengthened during the cold PDO phase at low levels, which tends to make equatorial warm water spread northward into the main RI region rsulting from meridional ocean advection associated with Ekman transport. Simultaneously, an anticyclonic wind anomaly is formed in the subtropical gyre of the WNP. This therefore may deepen the depth of the 26°C isotherm and directly increase TCHP over the main RI region. These thermodynamic effects associated with the cold PDO phase greatly support RI occurrence. The reverse is true during the warm PDO phase. The results also indicate that the VWS variability in the low wind shear zone along the monsoon trough may not be critical for the multidecadal modulation of RI events.
Commonly Used Drought Indices as Indicators of Soil Moisture in China
Authors: Wang Hongshuo , Rogers Jeffrey C. , Munroe Darla K. 
Published: March 2015

AbstractSoil moisture shortages adversely affecting agriculture are significantly associated with meteorological drought. Because of limited soil moisture observations with which to monitor agricultural drought, characterizing soil moisture using drought indices is of great significance. The relationship between commonly used drought indices and soil moisture is examined here using Chinese surface weather data and calculated station-based drought indices. Outside of northeastern China, surface soil moisture is more affected by drought indices having shorter time scales while deep-layer soil moisture is more related on longer index time scales. Multiscalar drought indices work better than drought indices from two-layer bucket models. The standardized precipitation evapotranspiration index (SPEI) works similarly or better than the standardized precipitation index (SPI) in characterizing soil moisture at different soil layers. In most stations in China, the Z index has a higher correlation with soil moisture at 0–5 cm than the Palmer drought severity index (PDSI), which in turn has a higher correlation with soil moisture at 90–100-cm depth than the Z index. Soil bulk density and soil organic carbon density are the two main soil properties affecting the spatial variations of the soil moisture–drought indices relationship. The study may facilitate agriculture drought monitoring with commonly used drought indices calculated from weather station data.
On the Hydrometeorological Changes of a Tropical Water Basin in the Caribbean and Its Sensitivity to Midterm Changes in Regional Climate
Authors: Comarazamy Daniel E. , González Jorge E. , Moshary Fred , Piasecki Michael 
Published: March 2015

AbstractGlobal climate change manifests in the Caribbean basin as increased SSTs, precipitation anomalies, and changes in atmospheric moisture content, among other effects. These regional climate changes have a profound impact on the local human, flora, and fauna populations. Such is the case of the Enriquillo basin, a highly sensitive ecosystem located in the southwestern region of the Caribbean island of Hispaniola. The major bodies of water in the basin, Lake Enriquillo and Lake Azuéi, show a shrinking and expanding pattern since the early 1980s. The surface area of Lake Enriquillo was observed to reach minimum values in 2004 (170 km2), shifting to a rapid expansion to its current levels (>350 km2 as of late 2013). Lake Azuéi is observed to grow at similar rates. This lake expansion could be attributed to regional climate change. Long-term regional climate data reflect increasing SSTs (~1°C), air temperatures (~0.37°C decade−1), dewpoint (~0.66°C decade−1), and precipitation (~30%); no reliable local precipitation records were found. Furthermore, local governments are being forced to issue evacuations, prompting one of the first cases of environmental refugees not caused by an extreme event (e.g., a hurricane or tsunami). The hypothesis of lake expansion in the Enriquillo basin as a regional response to climate change is further investigated with the use of an integrated regional atmospheric modeling system. Model results from simulations performed for years during the lakes’ lowest water levels (2003–04) and during their continued growth (2012–13) show increased total accumulated surface precipitation, atmospheric liquid water content, and an enhanced positive feedback system that produces orographic cloud cover in the surrounding tropical montane cloud forests as a consequence of the changing atmospheric and oceanic conditions.
The Canadian Land Data Assimilation System (CaLDAS): Description and Synthetic Evaluation Study
Authors: Carrera Marco L. , Bélair Stéphane , Bilodeau Bernard 
Published: March 2015

AbstractThe Canadian Land Data Assimilation System (CaLDAS) has been developed at the Meteorological Research Division of Environment Canada (EC) to better represent the land surface initial states in environmental prediction and assimilation systems. CaLDAS is built around an external land surface modeling system and uses the ensemble Kalman filter (EnKF) methodology. A unique feature of CaLDAS is the use of improved precipitation forcing through the assimilation of precipitation observations. An ensemble of precipitation analyses is generated by combining numerical weather prediction (NWP) model precipitation forecasts with precipitation observations. Spatial phasing errors to the NWP first-guess precipitation forecasts are more effective than perturbations to the precipitation observations in decreasing (increasing) the exceedance ratio (uncertainty ratio) scores and generating flatter, more reliable ranked histograms. CaLDAS has been configured to assimilate L-band microwave brightness temperature TB by coupling the land surface model with a microwave radiative transfer model. A continental-scale synthetic experiment assimilating passive L-band TBs for an entire warm season is performed over North America. Ensemble metric scores are used to quantify the impact of different atmospheric forcing uncertainties on soil moisture and TB ensemble spread. The use of an ensemble of precipitation analyses, generated by assimilating precipitation observations, as forcing combined with the assimilation of L-band TBs gave rise to the largest improvements in superficial soil moisture scores and to a more rapid reduction of the root-zone soil moisture errors. Innovation diagnostics show that the EnKF is able to maintain a sufficient forecast error spread through time, while soil moisture estimation error improvements with increasing ensemble size were limited.