bluuebunny/crossref_metadata_2025_split huggingface dataset:
Source modeling for Monte Carlo dose calculation of CT examinations with a radiotherapy treatment planning system
Authors: Källman Hans‐Erik , Holmberg Rickard , Andersson Jonas , Kull Love , Tranéus Erik , Ahnesjö Anders 
Published: October 2016

PurposeRadiation dose to patients undergoing examinations with Multislice Computed Tomography (MSCT) as well as Cone Beam Computed Tomography (CBCT) is a matter of concern. Risk management could benefit from efficient replace rational dose calculation tools. The paper aims to verify MSCT dose calculations using a Treatment Planning System (TPS) for radiotherapy and to evaluate four different variations of bow‐tie filter characterizations for the beam model used in the dose calculations.MethodsA TPS (RayStation™, RaySearch Laboratories, Stockholm, Sweden) was configured to calculate dose from a MSCT (GE Healthcare, Wauwatosa, WI, USA). The x‐ray beam was characterized in a stationary position the by measurements of the Half‐Value Layer (HVL) in aluminum and kerma along the principal axes of the isocenter plane perpendicular to the beam. A Monte Carlo source model for the dose calculation was applied with four different variations on the beam‐shaping bow‐tie filter, taking into account the different degrees of HVL information but reconstructing the measured kerma distribution after the bow‐tie filter by adjusting the photon sampling function. The resulting dose calculations were verified by comparison with measurements in solid water as well as in an anthropomorphic phantom.ResultsThe calculated depth dose in solid water as well as the relative dose profiles was in agreement with the corresponding measured values. Doses calculated in the anthropomorphic phantom in the range 26–55 mGy agreed with the corresponding thermo luminescence dosimeter (TLD) measurements. Deviations between measurements and calculations were of the order of the measurement uncertainties. There was no significant difference between the different variations on the bow‐tie filter modeling.ConclusionsUnder the assumption that the calculated kerma after the bow‐tie filter replicates the measured kerma, the central specification of the HVL of the x‐ray beam together with the kerma distribution can be used to characterize the beam. Thus, within the limits of the study, a flat bow‐tie filter with an HVL specified by the vendor suffices to calculate the dose distribution. The TPS could be successfully configured to replicate the beam movement and intensity modulation of a spiral scan with dose modulation, on the basis of the specifications available in the metadata of the digital images and the log file of the CT.
Dual-Reporter Mycobacteriophages (Φ
2
DRMs) Reveal Preexisting Mycobacterium tuberculosis Persistent Cells in Human Sputum
Authors: Jain Paras , Weinrick Brian C. , Kalivoda Eric J. , Yang Hui , Munsamy Vanisha , Vilcheze Catherine , Weisbrod Torin R. , Larsen Michelle H. , O’Donnell Max R. , Pym Alexander , Jacobs William R. 
Published: October 2016

ABSTRACT

Persisters are the minor subpopulation of bacterial cells that lack alleles conferring resistance to a specific bactericidal antibiotic but can survive otherwise lethal concentrations of that antibiotic. In infections with
Mycobacterium tuberculosis
, such persisters underlie the need for long-term antibiotic therapy and contribute to treatment failure in tuberculosis cases. Here, we demonstrate the value of
d
ual-
r
eporter
m
ycobacteriophages (Φ
2
DRMs) for characterizing
M. tuberculosis
persisters. The addition of isoniazid (INH) to exponentially growing
M. tuberculosis
cells consistently resulted in a 2- to 3-log decrease in CFU within 4 days, and the remaining ≤1% of cells, which survived despite being INH sensitive, were INH-tolerant persisters with a distinct transcriptional profile. We fused the promoters of several genes upregulated in persisters to the red fluorescent protein tdTomato gene in Φ
2
GFP10, a mycobacteriophage constitutively expressing green fluorescent protein (GFP), thus generating Φ
2
DRMs. A population enriched in INH persisters exhibited strong red fluorescence, by microscopy and flow cytometry, using a Φ
2
DRM with tdTomato controlled from the
dnaK
promoter. Interestingly, we demonstrated that, prior to INH exposure, a population primed for persistence existed in
M. tuberculosis
cells from both cultures and human sputa and that this population was highly enriched following INH exposure. We conclude that Φ
2
DRMs provide a new tool to identify and quantitate
M. tuberculosis
persister cells.

IMPORTANCE
Tuberculosis (TB) is again the leading cause of death from a single infectious disease, having surpassed HIV. The recalcitrance of the TB pandemic is largely due to the ability of the pathogen
Mycobacterium tuberculosis
to enter a persistent state in which it is less susceptible to antibiotics and immune effectors, necessitating lengthy treatment. It has been difficult to study persister cells, as we have lacked tools to isolate these rare cells. In this article, we describe the development of dual-reporter mycobacteriophages that encode a green fluorescent marker of viability and in which the promoters of genes we have identified as induced in the persister state are fused to a gene encoding a red fluorescent protein. We show that these tools can identify heterogeneity in a cell population that correlates with propensity to survive antibiotic treatment and that the proportions of these subpopulations change in
M. tuberculosis
cells within human sputum during the course of treatment.
Mechanical Strength and Inhibition of the Staphylococcus aureus Collagen-Binding Protein Cna
Authors: Herman-Bausier Philippe , Valotteau Claire , Pietrocola Giampiero , Rindi Simonetta , Alsteens David , Foster Timothy J. , Speziale Pietro , Dufrêne Yves F. 
Published: October 2016

ABSTRACT

The bacterial pathogen
Staphylococcus aureus
expresses a variety of cell surface adhesion proteins that bind to host extracellular matrix proteins. Among these, the collagen (Cn)-binding protein Cna plays important roles in bacterium-host adherence and in immune evasion. While it is well established that the A region of Cna mediates ligand binding, whether the repetitive B region has a dedicated function is not known. Here, we report the direct measurement of the mechanical strength of Cna-Cn bonds on living bacteria, and we quantify the antiadhesion activity of monoclonal antibodies (MAbs) targeting this interaction. We demonstrate that the strength of Cna-Cn bonds
in vivo
is very strong (~1.2 nN), consistent with the high-affinity “collagen hug” mechanism. The B region is required for strong ligand binding and has been found to function as a spring capable of sustaining high forces. This previously undescribed mechanical response of the B region is of biological significance as it provides a means to project the A region away from the bacterial surface and to maintain bacterial adhesion under conditions of high forces. We further quantified the antiadhesion activity of MAbs raised against the A region of Cna directly on living bacteria without the need for labeling or purification. Some MAbs are more efficient in blocking single-cell adhesion, suggesting that they act as competitive inhibitors that bind Cna residues directly involved in ligand binding. This report highlights the role of protein mechanics in activating the function of staphylococcal adhesion proteins and emphasizes the potential of antibodies to prevent staphylococcal adhesion and biofilm formation.

IMPORTANCE
Cna is a collagen (Cn)-binding protein from
Staphylococcus aureus
that is involved in pathogenesis. Currently, we know little about the functional role of the repetitive B region of the protein. Here, we unravel the mechanical strength of Cna in living bacteria. We show that single Cna-Cn bonds are very strong, reflecting high-affinity binding by the collagen hug mechanism. We discovered that the B region behaves as a nanospring capable of sustaining high forces. This unanticipated mechanical response, not previously described for any staphylococcal adhesin, favors a model in which the B region has a mechanical function that is essential for strong ligand binding. Finally, we assess the antiadhesion activity of monoclonal antibodies against Cna, suggesting that they could be used to inhibit
S. aureus
adhesion.
Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
Authors: Flores-Mireles Ana L. , Walker Jennifer N. , Potretzke Aaron , Schreiber Henry L. , Pinkner Jerome S. , Bauman Tyler M. , Park Alyssa M. , Desai Alana , Hultgren Scott J. , Caparon Michael G. 
Published: October 2016

ABSTRACT

Gram-positive bacteria in the genus
Enterococcus
are a frequent cause of catheter-associated urinary tract infection (CAUTI), a disease whose treatment is increasingly challenged by multiantibiotic-resistant strains. We have recently shown that
E. faecalis
uses the Ebp pilus, a heteropolymeric surface fiber, to bind the host protein fibrinogen as a critical step in CAUTI pathogenesis. Fibrinogen is deposited on catheters due to catheter-induced inflammation and is recognized by the N-terminal domain of EbpA (EbpA
NTD
), the Ebp pilus’s adhesin. In a murine model, vaccination with EbpA
NTD
confers significant protection against CAUTI. Here, we explored the mechanism of protection using passive transfer of immune sera to show that antisera blocking EbpA
NTD
-fibrinogen interactions not only is prophylactic but also can act therapeutically to reduce bacterial titers of an existing infection. Analysis of 55 clinical CAUTI, bloodstream, and gastrointestinal isolates, including
E. faecalis
,
E. faecium
, and vancomycin-resistant enterococci (VRE), revealed a diversity of levels of EbpA expression and fibrinogen-binding efficiency
in vitro
. Strikingly, analysis of 10 strains representative of fibrinogen-binding diversity demonstrated that, irrespective of EbpA levels, EbpA
NTD
antibodies were universally protective. The results indicate that, despite diversity in levels of fibrinogen binding, strategies that target the disruption of EbpA
NTD
-fibrinogen interactions have considerable promise for treatment of CAUTI.

IMPORTANCE
Urinary catheterization is a routine medical procedure, and it has been estimated that 30 million Foley catheters are used annually in the United States. Importantly, placement of a urinary catheter renders the patient susceptible to developing a catheter-associated urinary tract infection, accounting for 1 million cases per year. Additionally, these infections can lead to serious complications, including bloodstream infection and death.
Enterococcus
strains are a common cause of these infections, and management of enterococcal infections has been more difficult in recent years due to the development of antibiotic resistance and the ability of strains to disseminate, resulting in a major threat in hospital settings. In this study, we developed an antibiotic-sparing treatment that is effective against diverse enterococcal isolates, including vancomycin-resistant enterococci, during catheter-associated urinary tract infections.
The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA
Authors: Gorbunova Elena E. , Simons Matthew J. , Gavrilovskaya Irina N. , Mackow Erich R. 
Published: October 2016

ABSTRACT
Andes virus (ANDV) predominantly infects microvascular endothelial cells (MECs) and nonlytically causes an acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every pulmonary MEC is infected, MECs are enlarged, and infection results in vascular leakage and highly lethal pulmonary edema. We observed that MECs infected with the ANDV hantavirus or expressing the ANDV nucleocapsid (N) protein showed increased size and permeability by activating the Rheb and RhoA GTPases. Expression of ANDV N in MECs increased cell size by preventing tuberous sclerosis complex (TSC) repression of Rheb-mTOR-pS6K. N selectively bound the TSC2 N terminus (1 to 1403) within a complex containing TSC2/TSC1/TBC1D7, and endogenous TSC2 reciprocally coprecipitated N protein from ANDV-infected MECs. TSCs normally restrict RhoA-induced MEC permeability, and we found that ANDV infection or N protein expression constitutively activated RhoA. This suggests that the ANDV N protein alone is sufficient to activate signaling pathways that control MEC size and permeability. Further, RhoA small interfering RNA, dominant-negative RhoA(N19), and the RhoA/Rho kinase inhibitors fasudil and Y27632 dramatically reduced the permeability of ANDV-infected MECs by 80 to 90%. Fasudil also reduced the bradykinin-directed permeability of ANDV and Hantaan virus-infected MECs to control levels. These findings demonstrate that ANDV activation of RhoA causes MEC permeability and reveal a potential edemagenic mechanism for ANDV to constitutively inhibit the basal barrier integrity of infected MECs. The central importance of RhoA activation in MEC permeability further suggests therapeutically targeting RhoA, TSCs, and Rac1 as potential means of resolving capillary leakage during hantavirus infections.

IMPORTANCE
HPS is hallmarked by acute pulmonary edema, hypoxia, respiratory distress, and the ubiquitous infection of pulmonary MECs that occurs without disrupting the endothelium. Mechanisms of MEC permeability and targets for resolving lethal pulmonary edema during HPS remain enigmatic. Our findings suggest a novel underlying mechanism of MEC dysfunction resulting from ANDV activation of the Rheb and RhoA GTPases that, respectively, control MEC size and permeability. Our studies show that inhibition of RhoA blocks ANDV-directed permeability and implicate RhoA as a potential therapeutic target for restoring capillary barrier function to the ANDV-infected endothelium. Since RhoA activation forms a downstream nexus for factors that cause capillary leakage, blocking RhoA activation is liable to restore basal capillary integrity and prevent edema amplified by tissue hypoxia and respiratory distress. Targeting the endothelium has the potential to resolve disease during symptomatic stages, when replication inhibitors lack efficacy, and to be broadly applicable to other hemorrhagic and edematous viral diseases.
Multi-stakeholder perspectives of locally commissioned enhanced optometric services
Authors: Baker H , Harper R A , Edgar D F , Lawrenson J G 
Published: October 2016

ObjectivesTo explore views of all stakeholders (patients, optometrists, general practitioners (GPs), commissioners and ophthalmologists) regarding the operation of community-based enhanced optometric services.DesignQualitative study using mixed methods (patient satisfaction surveys, semi-structured telephone interviews and optometrist focus groups).SettingA minor eye conditions scheme (MECS) and glaucoma referral refinement scheme (GRRS) provided by accredited community optometrists.Participants189 patients, 25 community optometrists, 4 glaucoma specialist hospital optometrists (GRRS), 5 ophthalmologists, 6 GPs (MECS), 4 commissioners.ResultsOverall, 99% (GRRS) and 100% (MECS) patients were satisfied with their optometrists’ examination. The vast majority rated the following as ‘very good’; examination duration, optometrists’ listening skills, explanations of tests and management, patient involvement in decision-making, treating the patient with care and concern. 99% of MECS patients would recommend the service. Manchester optometrists were enthusiastic about GRRS, feeling fortunate to practise in a ‘pro-optometry’ area. No major negatives were reported, although both schemes were limited to patients resident within certain postcode areas, and some inappropriate GP referrals occurred (MECS). Communication with hospitals was praised in GRRS but was variable, depending on hospital (MECS). Training for both schemes was valuable and appropriate but should be ongoing. MECS GPs were very supportive, reporting the scheme would reduce secondary care referral numbers, although some MECS patients were referred back to GPs for medication. Ophthalmologists (MECS and GRRS) expressed very positive views and widely acknowledged that these new care pathways would reduce unnecessary referrals and shorten patient waiting times. Commissioners felt both schemes met or exceeded expectations in terms of quality of care, allowing patients to be seen quicker and more efficiently.ConclusionsLocally commissioned schemes can be a positive experience for all involved. With appropriate training, clear referral pathways and good communication, community optometrists can offer high-quality services that are highly acceptable to patients, health professionals and commissioners.
Improving the accuracy of electronic prescribing in West Bay Health Center in Qatar
Authors: Yousuf Wafaa , Elkomy Sheren , Soliman Mona , Al-Mansouri Noof , Salem Mohamed , Al-Ali Amal , H Mahmoud Mohamed , Elmahdi Hisham 
Published: October 2016

Primary healthcare in Qatar uses electronic prescribing to reduce the risk of medication errors. Electronic prescribing is supported by computerized Physician Order Entry systems through Cerner (electronic medical record system). There are still prescription errors, despite electronic prescribing being in place for one year at West Bay Health Center. West Bay Health Center is a famous primary healthcare center in Qatar. It is a training center for the family medicine residency program, which is accredited by the accreditation council of general medical education international (ACGME-I). It serves a population of about 98,000 in Qatar with 35 physicians and 12 pharmacists.The aim of this project was to decrease medication errors by 30% from baseline measurement (according to type of error) from October 2015 to March 2016. It was found that there was a discrepancy between the pharmacy medication list and the list within Cerner. A master drug index was created to eliminate the discrepancy. Training on the use of this index was provided through lectures and one to one education, with material also sent through email.We found that there was some resistance from the physician side and therefore introduced a second intervention. We sent out a survey to find out more about these difficulties and provided more training and education.Our results showed an decrease in the proportion of wrong dose errors from 11.8% to 10.6%, wrong name from 6.9% to 6.2%, wrong duration from 11.7% to 10.3%, and non-formulary drug errors from 2.6% to 1.6%.
A project to improve the management of patients on warfarin in a primary care setting through the introduction of a POC analysis
Authors: Karlsson Thore 
Published: October 2016

When noticed that patients commonly misunderstood their warfarin prescriptions when they were given by telephone. We found that the average TIR (time in range) (the relative time period the patients PT-INR value was in the therapeutic range) for patients decreased, and we noticed that the numbers of incidents increased. We made several interventions over a period of close to three years (2010-2012) to improve the quality of care, increase patients' TIRs, and decrease incidents.The interventions included; taking extra care when speaking to patients about their warfarin prescriptions on the phone and using an express mail delivery system to make sure patients got their letters in time. However, these changes made little difference to the measured results.In 2012, we introduced a point of care analysis. Through these simple actions TIR figures increased from 55 % to 75-80 % and fewer non-conformance reports were filed. Medical incidents, leading to costly hospitalizations, after the introduction of POC (point of care analysis) fell from six to two to three instances a year. The number of patients undergoing treatment and included in the study increased from 200 in 2008 to 250 in 2015.We found that these changes improved the quality of the care given without causing extra work for the staff. Patients were satisfied and the method has spread to other primary care centres.
Barriers and myths that limit the use of intrauterine contraception in nulliparous women: a survey of Brazilian gynaecologists
Authors: da Silva-Filho Agnaldo Lopes , Lira Josefina , Rocha Ana Luiza Lunardi , Carneiro Márcia Mendonça 
Published: October 2016

ABSTRACTObjectiveTo understand the extent to which barriers and misperceptions about intrauterine contraception (IUC) remain among Brazilian gynaecologists, particularly for nulliparous women.MethodsAn online survey was developed to assess Brazilian gynaecologists’ knowledge and attitudes towards IUC. Data collected included demographic and professional data, main barriers when considering IUC for women in general and/or nulliparous women, attitudes towards inclusion of IUC in contraceptive counselling, and opinions on what could increase IUC prescription for nulliparous women. A question regarding knowledge about WHO medical eligibility criteria (WHO MEC) was also included in the survey.Results101 gynaecologists completed the survey. The insertion rate in nulliparous women was 79.2%. Brazilian gynaecologists were more likely to consider IUC in counselling or provide it on request for parous than for nulliparous women (p&lt;0.05) and perceived more complications in nulliparous women. 74.2% of gynaecologists recognised a higher risk of pelvic inflammatory disease (PID)/infertility associated with IUC use in nulliparous women than in parous women. Difficult and painful insertion were also relevant for 83.2% and 77.3% of the gynaecologists, respectively. Respondents showed a high level of awareness of the WHO MEC classification.ConclusionsThe three most commonly reported barriers to considering IUC as a contraceptive option for nulliparous woman were concerns about PID and difficult or painful insertion. The challenge is to ensure that gynaecologists understand the evidence and do not disregard IUC as a potential option for nulliparous women.
The Natural Neighbor Radial Point Interpolation Method in Computational Fracture Mechanics: A 2D Preliminary Study
Authors: Belinha J. , Azevedo J. M. C. , Dinis L. M. J. S. , Natal Jorge R. M. 
Published: October 2016

In this work, the natural neighbor radial point interpolation method (NNRPIM) is extended to the numeric analysis of crack propagation problems. Here, the advanced discretization meshless technique is combined with a linear elastic crack growth algorithm. The algorithm simulates the crack propagation by displacing iteratively the crack tip, which consequently requires a local remeshing. In each iteration, it is estimated the stress state in the crack tip and afterwards the direction of the crack propagation is obtained considering the maximum circumferential stress criterion.The required local remeshing does not represent a numeric difficulty for the NNRPIM. The main advantage of the NNRPIM is its capability to fully discretize the problem domain using only an unstructured nodal distribution. Being a truly meshless method, the NNRPIM is able to define autonomously the nodal connectivity and the background integration mesh.The classic NNRPIM formulation permits to enforce the nodal connectivity by means of two kind of influence-cells: first degree influence-cells or second degree influence-cells. This work investigates the influence of the nodal connectivity on the simulated crack propagation path. Thus, demanding benchmark crack propagation examples are studied and the obtained results are compared with reference solutions available in the literature.