bluuebunny/crossref_metadata_2025_split huggingface dataset:
LPS Remodeling Triggers Formation of Outer Membrane Vesicles in
Salmonella
Authors: Elhenawy Wael , Bording-Jorgensen Michael , Valguarnera Ezequiel , Haurat M. Florencia , Wine Eytan , Feldman Mario F. 
Published: July 2016

ABSTRACT

Outer membrane vesicles (OMV) are proposed to mediate multiple functions during pathogenesis and symbiosis. However, the mechanisms responsible for OMV formation remain poorly understood. It has been shown in eukaryotic membranes that lipids with an inverted-cone shape favor the formation of positive membrane curvatures. Based on these studies, we formulated the hypothesis that lipid A deacylation might impose shape modifications that result in the curvature of the outer membrane (OM) and subsequent OMV formation. We tested the effect of lipid A remodeling on OMV biogenesis employing
Salmonella enterica
serovar Typhimurium as a model organism. Expression of the lipid A deacylase PagL resulted in increased vesiculation, without inducing an envelope stress response. Mass spectrometry analysis revealed profound differences in the patterns of lipid A in OM and OMV, with accumulation of deacylated lipid A forms exclusively in OMV. OMV biogenesis by intracellular bacteria upon macrophage infection was drastically reduced in a
pagL
mutant strain. We propose a novel mechanism for OMV biogenesis requiring lipid A deacylation in the context of a multifactorial process that involves the orchestrated remodeling of the outer membrane.

IMPORTANCE
The role of lipid remodeling in vesiculation is well documented in eukaryotes. Similarly, bacteria produce membrane-derived vesicles; however, the molecular mechanisms underlying their production are yet to be determined. In this work, we investigated the role of outer membrane remodeling in OMV biogenesis in
S
. Typhimurium. We showed that the expression of the lipid A deacylase PagL results in overvesiculation with deacylated lipid A accumulation exclusively in OMV. An
S
. Typhimurium Δ
pagL
strain showed a significant reduction in intracellular OMV secretion relative to the wild-type strain. Our results suggest a novel mechanism for OMV biogenesis that involves outer membrane remodeling through lipid A modification. Understanding how OMV are produced by bacteria is important to advance our understanding of the host-pathogen interactions.
Subducted lithosphere controls halogen enrichments in the Iceland mantle plume source
Authors: Halldórsson Sæmundur A. , Barnes Jaime D. , Stefánsson Andri , Hilton David R. , Hauri Erik H. , Marshall Edward W. 
Published: July 2016

Abstract
The chlorine isotope composition of Earth’s interior can place strong constraints on deep-Earth cycling of halogens and the origin of mantle chemical heterogeneity. However, all mantle-derived volcanic samples studied for Cl isotopes thus far originate from submarine volcanic systems, where the influence of seawater-derived Cl is pervasive. Here, we present Cl isotope data from subglacial volcanic glasses from Iceland, where the mid-ocean ridge system emerges above sea level and is free of seawater influence. The Iceland data display significant variability in δ37Cl values, from −1.8‰ to +1.4‰, and are devoid of regional controls. The absence of correlations between Cl and O isotope ratios and the lack of evidence for seawater-derived enrichments in Cl indicate that the variation in δ37Cl values in Icelandic basalts can be solely attributed to mantle heterogeneity. Indeed, positive correlations are evident between δ37Cl values and incompatible trace element ratios (e.g., La/Y), and long-lived radiogenic Pb isotope ratios. The data are consistent with the incorporation of altered lithosphere, including the uppermost sedimentary package, subducted into the Iceland mantle plume source, resulting in notable halogen enrichments in Icelandic basalts relative to lavas from adjacent mid-ocean ridges.
Incidence of adverse drug events in public and private hospitals in Riyadh, Saudi Arabia: the (ADESA) prospective cohort study
Authors: Aljadhey Hisham , Mahmoud Mansour A , Ahmed Yusuf , Sultana Razia , Zouein Salah , Alshanawani Sulafah , Mayet Ahmed , Alshaikh Mashael K , Kalagi Nora , Al Tawil Esraa , El Kinge Abdul Rahman , Arwadi Abdulmajid , Alyahya Maha , Murray Michael D , Bates David 
Published: July 2016

ObjectivesTo determine the incidence of adverse drug events (ADEs) and assess their severity and preventability in four Saudi hospitals.DesignProspective cohort study.SettingThe study included patients admitted to medical, surgical and intensive care units (ICUs) of four hospitals in Saudi Arabia. These hospitals include a 900-bed tertiary teaching hospital, a 400-bed private hospital, a 1400-bed large government hospital and a 350-bed small government hospital.ParticipantsAll patients (≥12 years) admitted to the study units over 4 months.Primary and secondary outcome measuresIncidents were collected by pharmacists and reviewed by independent clinicians. Reviewers classified the identified incidents as ADEs, potential ADEs (PADEs) or medication errors and then determined their severity and preventability.ResultsWe followed 4041 patients from admission to discharge. Of these, 3985 patients had complete data for analysis. The mean±SD age of patients in the analysed cohort was 43.4±19.0 years. A total of 1676 ADEs were identified by pharmacists during the medical chart review. Clinician reviewers accepted 1531 (91.4%) of the incidents identified by the pharmacists (245 ADEs, 677 PADEs and 609 medication errors with low risk of causing harm). The incidence of ADEs was 6.1 (95% CI 5.4 to 6.9) per 100 admissions and 7.9 (95% CI 6.9 to 8.9) per 1000 patient-days. The occurrence of ADEs was most common in ICUs (149 (60.8%)) followed by medical (67 (27.3%)) and surgical (29 (11.8%)) units. In terms of severity, 129 (52.7%) of the ADEs were significant, 91 (37.1%) were serious, 22 (9%) were life-threatening and three (1.2%) were fatal.ConclusionsWe found that ADEs were common in Saudi hospitals, especially in ICUs, causing significant morbidity and mortality. Future studies should focus on investigating the root causes of ADEs at the prescribing stage, and development and testing of interventions to minimise harm from medications.
Screening for cognitive impairment with the Montreal Cognitive Assessment in Chinese patients with acute mild stroke and transient ischaemic attack: a validation study
Authors: Zuo Lijun , Dong Yanhong , Zhu Rongyan , Jin Zhao , Li Zixiao , Wang Yilong , Zhao Xingquan , Sachdev Perminder , Zhang Wei , Wang Yongjun 
Published: July 2016

ObjectiveWe aimed to establish the cut-off point of the Montreal Cognitive Assessment (MoCA-Beijing) in screening for cognitive impairment (CI) within 2 weeks of mild stroke or transient ischaemic attack (TIA).MethodsA total of 80 acute mild ischaemic stroke patients and 22 TIA patients were recruited. They received the MoCA-Beijing and a formal neuropsychological test battery. CI was defined by 1.5 SD below the established norms on a formal neuropsychological test battery.ResultsMost stroke and TIA patients were in their 50s (53.95±11.43 years old), with greater than primary school level of education. The optimal cut-off point for MoCA-Beijing in discriminating patients with CI from those with no cognitive impairment (NCI) was 22/23 (sensitivity 85%, specificity 88%, positive predictive value=91%, negative predictive value=80%, classification accuracy=86%). The predominant cognitive deficits were characteristic of frontal-subcortical impairment, such as visuomotor speed (46.08%), attention/executive function (42.16%) and visuospatial ability (40.20%).ConclusionsA MoCA-Beijing cut-off score of 22/23 is optimally sensitive and specific for detecting CI after mild stroke, and TIA in the acute stroke phase, and is recommended for routine clinical practice.
Prostate-specific antigen testing in inner London general practices: are those at higher risk most likely to get tested?
Authors: Nderitu Paul , Van Hemelrijck Mieke , Ashworth Mark , Mathur Rohini , Hull Sally , Dudek Alexandra , Chowdhury Simon 
Published: July 2016

ObjectivesTo investigate the association between factors influencing prostate-specific antigen (PSA) testing prevalence including prostate cancer risk factors (age, ethnicity, obesity) and non-risk factors (social deprivation and comorbidity).SettingA cross-sectional database of 136 inner London general practices from 1 August 2009 to 31 July 2014.ParticipantsMen aged ≥40 years without prostate cancer were included (n=150 481).Primary outcomeLogistic regression analyses were used to estimate the association between PSA testing and age, ethnicity, social deprivation, body mass index (BMI) and comorbidity while adjusting for age, benign prostatic hypertrophy, prostatitis and tamsulosin or finasteride use.ResultsPSA testing prevalence was 8.2% (2013–2014), and the mean age was 54 years (SD 11). PSA testing was positively associated with age (OR 70–74 years compared to 40–44 years: 7.34 (95% CI 6.82 to 7.90)), ethnicity (black) (OR compared to white: 1.78 (95% CI 1.71 to 1.85)), increasing BMI and cardiovascular comorbidity. Testing was negatively associated with Chinese ethnicity and with increasing social deprivation.ConclusionsPSA testing among black patients was higher compared to that among white patients, which differs from lower testing rates seen in previous studies. PSA testing was positively associated with prostate cancer risk factors and non-risk factors. Association with non-risk factors may increase the risk of unnecessary invasive diagnostic procedures.
Mortality Reduction in Septic Shock by Plasma Adsorption (ROMPA): a protocol for a randomised clinical trial
Authors: Colomina-Climent Francisco , Giménez-Esparza Carola , Portillo-Requena Cristina , Allegue-Gallego José Manuel , Galindo-Martínez María , Mollà-Jiménez Cristina , Antón-Pascual José Luis , Rodríguez-Serra Manuel , Martín-Ruíz José Luis , Fernández-Arroyo Pablo Juan , Blasco-Císcar Eugenia María , Cánovas-Robles José , Herrera-Murillo Miguel , González-Hernández Enrique , Sánchez-Morán Fernando , Solera-Suárez Manuel , Torres-Tortajada Jesús , Nuñez-Martínez José María , Martín-Langerwerf David , Herrero-Gutiérrez Eugenio , Sebastián-Muñoz Isabel , Palazón-Bru Antonio , Gil-Guillén Vicente Francisco 
Published: July 2016

IntroductionThere is a lack of evidence in the efficacy of the coupled plasma filtration adsorption (CPFA) to reduce the mortality rate in septic shock. To fill this gap, we have designed the ROMPA study (Mortality Reduction in Septic Shock by Plasma Adsorption) to confirm whether treatment with an adequate dose of treated plasma by CPFA could confer a clinical benefit.Methods and analysisOur study is a multicentric randomised clinical trial with a 28-day and 90-day follow-up and allocation ratio 1:1. Its aim is to clarify whether the application of high doses of CPFA (treated plasma ≥0.20 L/kg/day) in the first 3 days after randomisation, in addition to the current clinical practice, is able to reduce hospital mortality in patients with septic shock in intensive care units (ICUs) at 28 and 90 days after initiation of the therapy. The study will be performed in 10 ICUs in the Southeast of Spain which follow the same protocol in this disease (based on the Surviving Sepsis Campaign). Our trial is designed to be able to demonstrate an absolute mortality reduction of 20% (α=0.05; 1−β=0.8; n=190(95×2)). The severity of the process, ensuring the recruitment of patients with a high probability of death (50% in the control group), will be achieved through an adequate stratification by using both severity scores and classical definitions of severe sepsis/septic shock and dynamic parameters. Our centres are fully aware of the many pitfalls associated with previous medical device trials. Trying to reduce these problems, we have developed a training programme to improve the CPFA use (especially clotting problems).Ethics and disseminationThe protocol was approved by the Ethics Committees of all the participant centres. The findings of the trial will be disseminated through peer-reviewed journals, as well as national and international conference presentations.Trial registration numberNCT02357433; Pre-results.
Computational fluid dynamics of cerebral aneurysm coiling using high-resolution and high-energy synchrotron X-ray microtomography: comparison with the homogeneous porous medium approach
Authors: Levitt Michael R , Barbour Michael C , Rolland du Roscoat Sabine , Geindreau Christian , Chivukula Venkat K , McGah Patrick M , Nerva John D , Morton Ryan P , Kim Louis J , Aliseda Alberto 
Published: July 2016

BackgroundComputational modeling of intracranial aneurysms provides insights into the influence of hemodynamics on aneurysm growth, rupture, and treatment outcome. Standard modeling of coiled aneurysms simplifies the complex geometry of the coil mass into a homogeneous porous medium that fills the aneurysmal sac. We compare hemodynamics of coiled aneurysms modeled from high-resolution imaging with those from the same aneurysms modeled following the standard technique, in an effort to characterize sources of error from the simplified model.MaterialsPhysical models of two unruptured aneurysms were created using three-dimensional printing. The models were treated with coil embolization using the same coils as those used in actual patient treatment and then scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the coil mass. Computational modeling of each aneurysm was performed using patient-specific boundary conditions. The coils were modeled using the simplified porous medium or by incorporating the X-ray imaged coil surface, and the differences in hemodynamic variables were assessed.ResultsX-ray microtomographic imaging of coils and incorporation into computational models were successful for both aneurysms. Porous medium calculations of coiled aneurysm hemodynamics overestimated intra-aneurysmal flow, underestimated oscillatory shear index and viscous dissipation, and over- or underpredicted wall shear stress (WSS) and WSS gradient compared with X-ray-based coiled computational fluid dynamics models.ConclusionsComputational modeling of coiled intracranial aneurysms using the porous medium approach may inaccurately estimate key hemodynamic variables compared with models incorporating high-resolution synchrotron X-ray microtomographic imaging of complex aneurysm coil geometry.
Physical Activity and Cancer Outcomes: A Precision Medicine Approach
Authors: Friedenreich Christine M. , Neilson Heather K. , Farris Megan S. , Courneya Kerry S. 
Published: July 2016

Abstract
There is increasing interest in applying a precision medicine approach to understanding exercise as a potential treatment for cancer. We aimed to inform this new approach by appraising epidemiologic literature relating postdiagnosis physical activity to cancer outcomes overall and by molecular/genetic subgroups. Across 26 studies of breast, colorectal, and prostate cancer patients, a 37% reduction was seen in risk of cancer-specific mortality, comparing the most versus the least active patients (pooled relative risk = 0.63; 95% confidence interval: 0.54–0.73). Risks of recurrence or recurrence/cancer-specific death (combined outcome) were also reduced based on fewer studies. We identified ten studies of associations between physical activity and cancer outcomes by molecular or genetic markers. Two studies showed statistically significant risk reductions in breast cancer mortality/recurrence for the most (versus least) physically active estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) patients, while others showed risk reductions among ER−PR− and triple-negative patients. In colorectal cancer, four studies showed statistically significant risk reductions in cancer-specific mortality for patients with high (versus low) physical activity and P21 expression, P27 expression, nuclear CTNNB1−, PTGS2 (COX-2)+, or IRS1 low/negative status. One prostate cancer study showed effect modification by Gleason score. As a means to enhance this evidence, future observational studies are needed that will measure physical activity objectively before and after diagnosis, use standardized definitions for outcomes, control for competing risks, assess nonlinear dose–response relations, and consider reverse causality. Ultimately, randomized controlled trials with clinical cancer outcomes and a correlative component will provide the best evidence of causality, relating exercise to cancer outcomes, overall and for molecular and genetic subgroups. Clin Cancer Res; 22(19); 4766–75. ©2016 AACR.
Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells
Authors: Choi Young Woo , Kang Moon Cheol , Seo Yong Bok , Namkoong Hong , Park Yunji , Choi Dong-Hoon , Suh You Suk , Lee Seung-Woo , Sung Young Chul , Jin Hyun-Tak 
Published: July 2016

AbstractPurpose: The induction of tissue-localized virus-specific CD8 T-cell response is essential for the development of an effective therapeutic vaccine against genital diseases, such as cervical cancer and genital herpes. Here, we aimed to elucidate the immunologic role of IL7 in the induction of mucosal cellular immunity.Experimental Design: IL7 was engineered through Fc fusion to enhance mucosal delivery across the genital epithelial barrier. The immunomodulatory role of IL7 was evaluated by monitoring the kinetics of various immune cells and measuring the expression of chemokines and cytokines after intravaginal administration of Fc-fused IL7 (IL7-Fc). The antitumor effects of intramuscular human papillomavirus (HPV) DNA vaccine or topical IL7-Fc alone or in a combinational regimen on mice survival were compared using a orthotopic cervical cancer model.Results: Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells. Importantly, in this murine cervical cancer model, topical administration of IL7-Fc after intramuscular HPV DNA vaccination increases the number of HPV-specific CD8 T cells in the genital mucosa, but not in the spleen, leading to stronger antitumor activity than the HPV DNA vaccine alone.Conclusions: Our findings provide an important insight into the immunomodulatory role of IL7-Fc via topical application and the design of therapeutic vaccine regimen that induces effective genital–mucosal CD8 T-cell responses. Clin Cancer Res; 22(23); 5898–908. ©2016 AACR.
Trajectories of Stress, Depressive Symptoms, and Immunity in Cancer Survivors: Diagnosis to 5 Years
Authors: Andersen Barbara L. , Goyal Neha Godiwala , Westbrook Travis D. , Bishop Brenden , Carson William E. 
Published: July 2016

Abstract
Purpose: Five-year disease endpoint trajectories are available for every cancer site. In contrast, there are few longitudinal, biobehavioral studies of survivors extending beyond the first or second year following diagnosis. This gap is addressed with stress, depressive symptom, and immunity data from breast cancer patients followed continuously for 5 years.
Experimental Design: Women (N = 113) diagnosed and surgically treated for breast cancer and awaiting adjuvant therapy completed self-report measures of stress and depressive symptoms and provided blood for immune assays [natural killer cell cytotoxicity (NKCC) and T-cell blastogenesis]. Assessments (N = 12) were repeated every 4 to 6 months for 5 years.
Results: Multiphase linear mixed models show phases of change and identified specific time points of change. Cancer stress shows two distinct phases of decline, with the change point being 12 months. In contrast, a steep decline in depressive symptoms occurs by 7 months, with stable, low levels thereafter. NKCC shows a steady upward trajectory through 18 months and upper limit stability thereafter, whereas there was no reliable trajectory for T-cell blastogenesis.
Conclusions: For the first time, trajectories and specific time points of change in biobehavioral data for breast cancer survivors are provided, traced through 5 years. Following diagnosis, the breast survivor experience is one of a co-occurrence of change (recovery) in psychologic and innate immunity markers from diagnosis to18 months, and a pattern of stability (depression, NKCC) or continued improvement (stress) through year 5. These data provide new directions for survivorship care and detail of the biobehavioral trajectory. Clin Cancer Res; 23(1); 52–61. ©2016 AACR.
Predictors of Long-Term Outcomes in Asymptomatic Patients With Severe Aortic Stenosis and Preserved Left Ventricular Systolic Function Undergoing Exercise Echocardiography
Authors: Masri Ahmad , Goodman Andrew L. , Barr Tyler , Grimm Richard A. , Sabik Joseph F. , Gillinov A. Marc , Rodriguez L. Leonardo , Svensson Lars G. , Griffin Brian P. , Desai Milind Y. 
Published: July 2016

Background—
In asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction, we sought to assess incremental prognostic utility of exercise stress echocardiography.

Methods and Results—

We studied 533 such patients (age, 66±13 years; 78% men; 31% with coronary artery disease) who underwent exercise stress echocardiography between 2001 and 2012. Clinical, echocardiographic, and exercise variables (metabolic equivalents [METs], % of age–sex–predicted METs and heart rate recovery at first minute post exercise) were recorded. The end point was all-cause mortality. The Society of Thoracic Surgeons score, left ventricular ejection fraction, mean resting aortic valve (AV) gradient, indexed AV area, METs, and heart rate recovery were 2.9±3%, 58±4%, 35±11 mm Hg, 0.47±0.1 cm
2
/m
2
, 7.8±3, and 26±12 bpm, respectively. Only 50% achieved >100%, whereas 26% achieved <85% age–sex–predicted METs. There were no major exercise stress echocardiography-related complications. Over 6.9±3 years, 341 (64%) underwent AV replacement (54% isolated), and there were 104 (20%) deaths. On multivariable Cox proportional hazard survival analysis, a higher Society of Thoracic Surgeons score (hazard ratio, 1.21), lower % age–sex–predicted METs (hazard ratio 1.15), and slower heart rate recovery (hazard ratio, 1.22) were associated with higher longer-term mortality, whereas AV replacement (time-dependent covariate, hazard ratio, 0.26) was associated with improved survival. The addition of % age–sex–predicted METs to the Society of Thoracic Surgeons score resulted in significant reclassification of longer-term mortality risk (integrated discrimination index, 0.07 [0.03–0.11;
P
<0.001).

Conclusions—
In asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction undergoing exercise stress echocardiography, a lower % of age–sex–predicted METs and slower heart rate recovery were associated with longer-term mortality, whereas AV replacement was associated with improved survival.