bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a multi‐center randomised clinical trial on prophylactic transfusion of fresh frozen plasma: implications for future trials
Authors: Müller M. C. A. , de Haan R. J. , Vroom M. B. , Juffermans N. P. 
Published: September 2014

SUMMARYBackgroundProphylactic use of fresh frozen plasma (FFP) in critically ill patients with a coagulopathy is common. However, a lack of evidence of efficacy has resulted in a call for trials on the benefit of FFP in these patients. To date, conducting a trial on this subject has not been successful. Recently, a multi‐center randomised trial was stopped prematurely due to slow inclusion.ObjectiveTo assess clinicians' opinions regarding a trial on prophylactic administration of FFP in coagulopathic critically ill patients who need to undergo an intervention.MethodsA survey among 55 intensivists who all participated in a randomised trial on the risks and benefits of FFP in critically ill patients.ResultsResponse rate was 84%. Majority of respondents indicated that international normalised ratio (INR) should be assessed before insertion of a central venous catheter (CVC) (61%), chest tube (89%) or tracheostomy (91%). Reasons to withhold transfusion of FFP to non‐bleeding critically ill patients are risk of transfusion‐related acute lung injury (TRALI) (46%), fluid overload (39%) and allergic reaction (24%). Although, the majority of respondents expressed the opinion that the trial was clinically relevant, 56% indicated that ≥1 patient subgroups should have been excluded from participation.ConclusionIntensivists express the need for more evidence on the prophylactic use of FFP in coagulopathic critically ill patients. However, lack of knowledge about FFP and personal beliefs about the preferable transfusion strategy among clinicians, resulted in premature termination of a clinical trial on this topic.
In Vitro
Selection of Neisseria gonorrhoeae Mutants with Elevated MIC Values and Increased Resistance to Cephalosporins
Authors: Johnson Steven R. , Grad Yonatan , Ganakammal Satishkumar Ranganathan , Burroughs Mark , Frace Mike , Lipsitch Marc , Weil Ryan , Trees David 
Published: September 2014

ABSTRACT

Strains of
Neisseria gonorrhoeae
with mosaic
penA
genes bearing novel point mutations in
penA
have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third-generation cephalosporins. Here we report the
in vitro
isolation of two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic
penA
gene, and the second contains an insertion mutation in
pilQ
.
Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis
Authors: Dolton Michael J. , Brüggemann Roger J. M. , Burger David M. , McLachlan Andrew J. 
Published: September 2014

ABSTRACT
Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.
Identification of Genomic Binding Sites for Candida glabrata Pdr1 Transcription Factor in Wild-Type and ρ
0
Cells
Authors: Paul Sanjoy , Bair Thomas B. , Moye-Rowley W. Scott 
Published: September 2014

ABSTRACT

The fungal pathogen
Candida glabrata
is an emerging cause of candidiasis in part owing to its robust ability to acquire tolerance to the major clinical antifungal drug fluconazole. Similar to the related species
Candida albicans
,
C. glabrata
most typically gains azole tolerance via transcriptional induction of a suite of resistance genes, including a locus encoding an ABCG-type ATP-binding cassette (ABC) transporter that is referred to as
CDR1
in
Candida
species. In
C. glabrata
,
CDR1
expression is controlled primarily by the activity of a transcriptional activator protein called Pdr1. Strains exhibiting reduced azole susceptibility often contain substitution mutations in
PDR1
that in turn lead to elevated mRNA levels of target genes with associated azole resistance. Pdr1 activity is also induced upon loss of the mitochondrial genome status and upon challenge by azole drugs. While extensive analyses of the transcriptional effects of Pdr1 have identified a number of genes that are regulated by this factor, we cannot yet separate direct from indirect target genes. Here we used chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-seq) to identify the promoters and associated genes directly regulated by Pdr1. These genes include many that are shared with the yeast
Saccharomyces cerevisiae
but others that are unique to
C. glabrata
, including the ABC transporter-encoding locus
YBT1
, genes involved in DNA repair, and several others. These data provide the outline for understanding the primary response genes involved in production of Pdr1-dependent azole resistance in
C. glabrata
.
Antiepileptic drug treatment of rolandic epilepsy and Panayiotopoulos syndrome: clinical practice survey and clinical trial feasibility
Authors: Mellish Louise C , Dunkley Colin , Ferrie Colin D , Pal Deb K 
Published: September 2014

BackgroundThe evidence base for management of childhood epilepsy is poor, especially for the most common specific syndromes such as rolandic epilepsy (RE) and Panayiotopoulos syndrome (PS). Considerable international variation in management and controversy about non-treatment indicate the need for high quality randomised controlled trials (RCT). The aim of this study is, therefore, to describe current UK practice and explore the feasibility of different RCT designs for RE and PS.MethodsWe conducted an online survey of 590 UK paediatricians who treat epilepsy. Thirty-two questions covered annual caseload, investigation and management practice, factors influencing treatment, antiepileptic drug preferences and hypothetical trial design preferences.Results132 responded (22%): 81% were paediatricians and 95% at consultant seniority. We estimated, annually, 751 new RE cases and 233 PS cases. Electroencephalography (EEG) is requested at least half the time in approximately 70% of cases; MRI brain at least half the time in 40%–65% cases and neuropsychological evaluation in 7%–8%. Clinicians reported non-treatment in 40%: main reasons were low frequency of seizures and parent/child preferences. Carbamazepine is the preferred older, and levetiracetam the preferred newer, RCT arm. Approximately one-half considered active and placebo designs acceptable, choosing seizures as primary and cognitive/behavioural measures as secondary outcomes.ConclusionsManagement among respondents is broadly in line with national guidance, although with possible overuse of brain imaging and underuse of EEG and neuropsychological assessments. A large proportion of patients in the UK remains untreated, and clinicians seem amenable to a range of RCT designs, with carbamazepine and levetiracetam the preferred active drugs.
Acute tear of the fascia cruris at the attachment to the Achilles tendon: a new diagnosis
Authors: Webborn Nick , Morrissey Dylan , Sarvananthan Kasthuri , Chan Otto 
Published: September 2014

BackgroundThe fascia cruris encloses the posterior structures of the calf and connects to the paratenon and the Achilles tendon. We describe the clinical presentation, ultrasound imaging characteristics and the time to the recovery of tears of the fascia cruris at the attachment to the Achilles tendon.MethodsRetrospective review of 11 tears of the fascia cruris in the different legs as separate events in 9 patients (6 male and 3 female, mean age 35.52 years, range 11–48) identified using diagnostic ultrasound, after presenting with Achillodynia.Results11 participants presented at a mean of 4.5 weeks (range 0.5–12) after onset of symptoms. The left Achilles was more commonly injured than the right (7 : 4) and the lateral side more than the medial (6 : 4) with one case with medial and lateral presentation. Clinically, there was swelling and tenderness over the medial or lateral border in the mid to upper portion of the Achilles. 7 of the 11 (63.6%) had functional overpronation. Ultrasound appearances of a tear were identified as hypoechoic area extending from the medial or lateral border of the Achilles extending along the anatomical plane of the fascia cruris. Average return to activity was 5.2 weeks (range 1–22). Participants presenting later had longer recovery but all participants returned to full activity (r=0.4).ConclusionsThis is the first description of the clinical details and sonographic findings of a tear to the fascia cruris at its attachment to the Achilles tendon. This needs to be considered as a cause of Achillodynia in athletes as recognition will affect the management.
Ambulatory blood pressure adds little to Framingham Risk Score for the primary prevention of cardiovascular disease in older men: secondary analysis of observational study data
Authors: Bell Katy J L , Beller Elaine , Sundström Johan , McGeechan Kevin , Hayen Andrew , Irwig Les , Neal Bruce , Glasziou Paul 
Published: September 2014

ObjectiveTo determine the incremental value of ambulatory blood pressure (BP) in predicting cardiovascular risk when the Framingham Risk Score (FRS) is known.MethodsWe included 780 men without cardiovascular disease from the Uppsala Longitudinal Study of Adult Men, all aged approximately 70 years at baseline. We first screened ambulatory systolic BP (ASBP) parameters for their incremental value by adding them to a model with 10-year FRS. For the best ASBP parameter we estimated HRs and changes in discrimination, calibration and reclassification. We also estimated the difference in the number of men started on treatment and in the number of men protected against a cardiovascular event.ResultsMean daytime ASBP had the highest incremental value; adding other parameters did not yield further improvements. While ASBP was an independent risk factor for cardiovascular disease, addition to FRS led to only small increases to the overall model fit, discrimination (a 1% increase in the area under the receiver operating characteristic (ROC) curve), calibration and reclassification. We estimated that for every 10 000 men screened with ASBP, 141 fewer would start a new BP-lowering treatment (95% CI 62 to 220 less treated), but this would result in 7 fewer cardiovascular events prevented over the subsequent 10 years (95% CI 21 fewer events prevented to 7 more events prevented).ConclusionsIn addition to a standard cardiovascular risk assessment it is not clear that ambulatory BP measurement provides further incremental value. The clinical role of ambulatory BP requires ongoing careful consideration.
Geographic variations in sleep duration: a multilevel analysis from the Boston Area Community Health (BACH) Survey
Authors: Fang Shona C , Subramanian S V , Piccolo Rebecca , Yang May , Yaggi H Klar , Bliwise Donald L , Araujo Andre B 
Published: September 2014

BackgroundSleep plays an important role in health and varies by social determinants. Little is known, however, about geographic variations in sleep and the role of individual-level and neighbourhood-level factors.MethodsWe used a multilevel modelling approach to quantify neighbourhood variation in self-reported sleep duration (very short <5 h; short 5–6.9 h; normative 7–8.9 h; long ≥9 h) among 3591 participants of the Boston Area Community Health Survey. We determined whether geographic variations persisted with control for individual-level demographic, socioeconomic status (SES) and lifestyle factors. We then determined the role of neighbourhood SES (nSES) in geographic variations. Additional models considered individual health factors.ResultsBetween neighbourhood differences accounted for a substantial portion of total variability in sleep duration. Neighbourhood variation persisted with control for demographics, SES and lifestyle factors. These characteristics accounted for a portion (6–20%) of between-neighbourhood variance in very short, short and long sleep, while nSES accounted for the majority of the remaining between-neighbourhood variances. Low and medium nSES were associated with very short and short sleep (eg, very short sleep OR=2.08; 95% CI 1.38 to 3.14 for low vs high nSES), but not long sleep. Further inclusion of health factors did not appreciably increase the amount of between-neighbourhood variance explained nor did it alter associations.ConclusionsSleep duration varied by neighbourhood in a diverse urban setting in the northeastern USA. Individual-level demographics, SES and lifestyle factors explained some geographic variability, while nSES explained a substantial amount. Mechanisms associated with nSES should be examined in future studies to help understand and reduce geographic variations in sleep.
Pipeline endovascular device for the treatment of intracranial aneurysms at the level of the circle of Willis and beyond: multicenter experience
Authors: Martínez-Galdámez M , Romance A , Vega P , Vega A , Caniego J L , Paul L , Linfante I , Dabus G 
Published: September 2014

Background and purposeThe aim of our study was to evaluate the safety and efficacy of the pipeline endovascular device for the treatment of anterior circulation aneurysms at the level of the circle of Willis and beyond.MethodsA consecutive series of 25 patients (24 unruptured and one ruptured) with anterior circulation aneurysms treated with a pipeline endovascular device were included in the analysis.ResultsWe found two minor clinical events (resolved within 7 days of the procedure), one major event (symptoms present after 7 days), and no mortality. There were no aneurysm ruptures or parenchymal hemorrhages during follow-up. The modified Rankin Scale (mRS) scores at 3 and 6 months did not change from the prior mRS score for all cases except 1. There was one asymptomatic periprocedural event. There were three intraprocedural complications which resolved without clinical consequences. Six month follow-up angiograms were obtained for 22 aneurysms, showing complete occlusion in 14 (64%) and significantly decreased residual filling in 8 (36%). The status of branches originating from the aneurysm sacs was evaluated in 14 angiograms: 11 were patent (79%), 2 had moderate reduction (14%) and 1 (7%) was occluded. We found six cases of in-stent stenosis (27%) on 6 month DSA, with only one symptomatic case.ConclusionsThe pipeline embolization device provides a feasible and technically safe solution for aneurysms at and beyond the circle of Willis. Preliminary results are promising but larger series with longer term follow-up examinations are required to show the long term safety and durability of this treatment alternative.
Development of a novel in vitro method for drug development for fish; application to test efficacy of antimicrosporidian compounds
Authors: Saleh M. , Kumar G. , Abdel‐Baki A‐A. , Dkhil M. , El‐Matbouli M. , Al‐Quraishy S. 
Published: September 2014

Few drugs are approved for treating diseases caused by parasites in minor species such as fish. This is due, in part, to the expense of drug development and to the comparatively small market. In vivo effectiveness trials for antiparasitic drugs are costly, time consuming and require ethics approval, therefore an in vitro screening approach is a cost‐effective alternative to finding promising drug candidates. We developed an in vitro testing system to test antimicrosporidial compounds against a microsporidian pathogen Heterosporis saurida. Five antiparasitic compounds, albendazole, fumagillin, TNP‐70, nitazoxanide and lufenuron, were assayed for antimicrosporidial activity. All compounds reduced the number of H saurida spores in infected cells when applied at a concentration that did not appear to be toxic to the host cells. Albendazole inhibited replication of H saurida by >60 per cent, fumagillin and its analogue TNP‐470 inhibited H saurida >80 per cent, nitazoxanide and lufenuron inhibited growth >70 per cent. The data suggest that both fumagillin and its analogous TNP‐70 hold the best promise as therapeutic agents against H saurida. The ability to use fish cell cultures to assess drugs against H saurida demonstrates an approach that may be helpful to evaluate other drugs on different microsporidia and host cells.
Hypothalamic‐anterior pituitary hormone deficiencies following traumatic brain injury in dogs
Authors: Murtagh K. , Arrol L. , Goncalves R. , Granger N. , German A. J. , Smith P. M. 
Published: September 2014

Traumatic brain injury is an important cause of hypopituitarism in human beings, but limited information exists in the veterinary literature regarding this condition. The primary study objective was to investigate whether hypothalamic‐anterior pituitary axis dysfunction exists following traumatic brain injury in 17 client owned dogs. In this retrospective, observational, open, cohort study, information about dogs presented to four separate referral centres between April 2008 and October 2013 was reviewed. Cases were included if they had suffered from non‐fatal traumatic brain injury, resulting in neurological dysfunction, and follow‐up evaluation included measurement of the serum concentration of insulin‐like growth factor 1 (IGF‐1), endogenous adrenocorticotrophic hormone (ACTH), basal cortisol, thyroid‐stimulating hormone, total thyroxine (TT4) and, if appropriate, free thyroxine. Decreased IGF‐1 concentration was the most common abnormality detected (7/17, 41 per cent; median 132 ng/ml, range <15–536), followed by a decreased TT4concentration (4/17, 23 per cent; median 19, range 4–49). Basal cortisol concentration was less than 20 nmol/l in two cases (2/17, 12 per cent; median 65, range <20–1735), with concurrently undetectable ACTH (<5 pg/ml). This study demonstrates that dogs with a history of traumatic brain injury can develop endocrine abnormalities indicative of hypothalamic‐anterior pituitary dysfunction.
Estimation of horizontal stress magnitudes using sonic data from vertical and deviated wellbores in a depleted reservoir
Authors: Sinha Bikash K. , Wendt Anke S. 
Published: September 2014

Abstract
Changes in the reservoir rock stresses caused by large variations in the pore pressure play an important role in maintaining reservoir mechanical stability and therefore are important input to drilling and completion decisions. Producer wells are often designed with complex trajectories that include both nearly vertical and deviated sections to maximize hydrocarbon productivity. A new inversion algorithm estimates the maximum and minimum horizontal stresses in the formation using radial profiles of the three shear moduli in the two axial and cross-sectional planes of a vertical or deviated borehole. This algorithm inverts differences in the far-field shear moduli with the two difference equations obtained from radial profiles of the dipole shear moduli in the two axial planes between near and far radial positions from the borehole surface. Borehole stresses are related to the far-field principal stresses in terms of borehole azimuth and deviation. Difference equations for the shear moduli and corresponding stresses use radial positions away from the borehole surface that do not exhibit any plastic deformation. Borehole sonic data acquired from a vertical and deviated wellbores have been inverted to obtain formation stress magnitudes for a given change in the reservoir pressure in a depleted, highly faulted, high-pressure and high-temperature North Sea field. Estimates of the minimum horizontal stress magnitudes from this inversion algorithm are consistent with an independent estimate obtained from a standard minifrac test.
Automated Detection of Client-State Manipulation Vulnerabilities
Authors: Møller Anders , Schwarz Mathias 
Published: September 2014

Web application programmers must be aware of a wide range of potential security risks. Although the most common pitfalls are well described and categorized in the literature, it remains a challenging task to ensure that all guidelines are followed. For this reason, it is desirable to construct automated tools that can assist the programmers in the application development process by detecting weaknesses. Many vulnerabilities are related to Web application code that stores references to application state in the generated HTML documents to work around the statelessness of the HTTP protocol. In this article, we show that such client-state manipulation vulnerabilities are amenable to tool-supported detection.
We present a static analysis for the widely used frameworks Java Servlets, JSP, and Struts. Given a Web application archive as input, the analysis identifies occurrences of client state and infers the information flow between the client state and the shared application state on the server. This makes it possible to check how client-state manipulation performed by malicious users may affect the shared application state and cause leakage or modifications of sensitive information. The warnings produced by the tool help the application programmer identify vulnerabilities before deployment. The inferred information can also be applied to configure a security filter that automatically guards against attacks at runtime. Experiments on a collection of open-source Web applications indicate that the static analysis is able to effectively help the programmer prevent client-state manipulation vulnerabilities. The analysis detects a total of 4,802 client-state parameters in ten applications, whereof 4,437 are classified as safe and 241 reveal exploitable vulnerabilities.