bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric Oxide Disrupts Zinc Homeostasis in Salmonella enterica Serovar Typhimurium
Authors: Frawley Elaine R. , Karlinsey Joyce E. , Singhal Anshika , Libby Stephen J. , Doulias Paschalis-Thomas , Ischiropoulos Harry , Fang Ferric C. 
Published: August 2018

ABSTRACT

Nitric oxide (NO·) produced by mammalian cells exerts antimicrobial actions that result primarily from the modification of protein thiols (
S
-nitrosylation) and metal centers. A comprehensive approach was used to identify novel targets of NO· in
Salmonella enterica
serovar Typhimurium (
S.
Typhimurium). Newly identified targets include zinc metalloproteins required for DNA replication and repair (DnaG, PriA, and TopA), protein synthesis (AlaS and RpmE), and various metabolic activities (ClpX, GloB, MetE, PepA, and QueC). The cytotoxic actions of free zinc are mitigated by the ZntA and ZitB zinc efflux transporters, which are required for
S.
Typhimurium resistance to zinc overload and nitrosative stress
in vitro
. Zinc efflux also ameliorates NO·-dependent zinc mobilization following internalization by activated macrophages and is required for virulence in NO·-producing mice, demonstrating that host-derived NO· causes zinc stress in intracellular bacteria.

IMPORTANCE
Nitric oxide (NO·) is produced by macrophages in response to inflammatory stimuli and restricts the growth of intracellular bacteria. Mechanisms of NO·-dependent antimicrobial actions are incompletely understood. Here, we show that zinc metalloproteins are important targets of NO· in
Salmonella
, including the DNA replication proteins DnaG and PriA, which were hypothesized to be NO· targets in earlier studies. Like iron, zinc is a cofactor for several essential proteins but is toxic at elevated concentrations. This study demonstrates that NO· mobilizes free zinc in
Salmonella
and that specific efflux transporters ameliorate the cytotoxic effects of free zinc during infection.
Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels
Authors: Feuillie Cécile , Vitry Pauline , McAleer Maeve A. , Kezic Sanja , Irvine Alan D. , Geoghegan Joan A. , Dufrêne Yves F. 
Published: August 2018

ABSTRACT

The bacterial pathogen
Staphylococcus aureus
plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by
S. aureus
exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to
S. aureus
adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions.
S. aureus
bacteria isolated from AD skin bind much more strongly to corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by
S. aureus
. Collectively, our findings demonstrate that patient NMF levels regulate the strength of
S. aureus
-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments.

IMPORTANCE
Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of
Staphylococcus aureus
to skin corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents.
Development of a model to predict 5-year risk of severe hypoglycemia in patients with type 2 diabetes
Authors: Chow Lisa S , Zmora Rachel , Ma Sisi , Seaquist Elizabeth R , Schreiner Pamela J 
Published: August 2018

ObjectiveWe constructed a predictive model of long-term risk for severe hypoglycemia (SH: hypoglycemia requiring assistance) in patients with type 2 diabetes (T2DM).Research design and methodsData from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (original n=10 251, n=5135 used in the current analysis), a randomized, multicenter, double 2×2 factorial design study examining the effect of glycemic, blood pressure, and lipid control on cardiovascular outcomes in patients with diagnosed T2DM, were used. Over the follow-up (3.76±1.12 years), the ACCORD participants experienced 607 incident SH events. Cox regression was used to identify the SH risk prediction model.ResultsWe identified 17 predictors—glycemic management, age, race, education, waist circumference, medications (insulin, antihypertensive, HMG-CoA reductase inhibitors, sulfonylurea, biguanide and meglitinide), years since diabetes diagnosis, history of hypoglycemia in the last week, systolic blood pressure, diastolic blood pressure, serum creatinine, and urinary albumin creatinine ratio—to construct a prediction model for SH (c-statistic=0.782). Using this information, we derived point scores to estimate the 5-year risk for SH in individual patients with T2DM. After adjusting for other variables in the model, the three strongest predictors for SH over 5 years were intensive glycemic management (HR=2.37, 95% CI 1.99 to 2.83), insulin use (HR=2.14, 95% CI 1.77 to 2.59), and antihypertensive medication use (HR=1.90, 95% CI 1.26 to 2.86).ConclusionUsing the ACCORD data, we identified attributes to predict 5-year risk of SH in patients with T2DM, which warrant evaluation in broader populations to determine applicability.
Protocol for a mixed-methods evaluation of a massive open online course on real world evidence
Authors: Meinert Edward , Alturkistani Abrar , Brindley David , Carter Alison , Wells Glenn , Car Josip 
Published: August 2018

IntroductionIncreasing number of Massive Open Online Courses (MOOCs) are being used to train learners at scale in various healthcare-related skills. However, many challenges in course delivery require further understanding, for example, factors exploring the reasons for high MOOC dropout rates, recorded low social interaction between learners and the lack of understanding of the impact of a course facilitators’ presence in course engagement. There is a need to generate further evidence to explore these detriments to MOOC course delivery to enable enhanced course learning design. The proposed mixed-methods evaluation of the MOOC was determined based on the MOOC’s aims and objectives and the methodological approaches used to evaluate this type of a course. The MOOC evaluation will help appraise the effectiveness of the MOOC in delivering its intended objectives. This protocol aims to describe the design of a study evaluating learners knowledge, skills and attitudes in a MOOCs about data science for healthcare.Methods and analysisStudy participants will be recruited from learners who have registered for the MOOC. On registration, learners will be given an opportunity to opt into the study and complete informed consent. Following completion of the course, study participants will be contacted to complete semistructured interviews. Interviews will be transcribed and coded using thematic analysis, with data analysed using two evaluation models: (1) the reach, effectiveness, adoption, implementation, maintenance framework and the (2) Kirkpatrick model drawing data from pre and post-course surveys and post-MOOC semi-structured interviews. The primary goal of the evaluation is to appraise participants' knowledge, skills and attitude after taking the MOOC.Ethics and disseminationEthics approval for this study was obtained from Imperial College London through the Education Ethics Review Process (EERP) (EERP1617-030). A summary of the research findings will be reported through a peer-reviewed journal and will be presented at an international conference.
Frameworks and quality measures used for debriefing in team-based simulation: a systematic review
Authors: Endacott Ruth , Gale Thomas , O’Connor Anita , Dix Samantha 
Published: August 2018

ObjectivesThe skill of the debriefer is known to be the strongest independent predictor of the quality of simulation encounters yet educators feel underprepared for this role. The aim of this review was to identify frameworks used for debriefing team-based simulations and measures used to assess debriefing quality.MethodsWe systematically searched PubMed, CINAHL, MedLine and Embase databases for simulation studies that evaluated a debriefing framework. Two reviewers evaluated study quality and retrieved information regarding study methods, debriefing framework, outcome measures and debriefing quality.ResultsA total of 676 papers published between January 2003 and December 2017 were identified using the search protocol. Following screening of abstracts, 37 full-text articles were assessed for eligibility, 26 studies met inclusion criteria for quality appraisal and 18 achieved a sufficiently high-quality score for inclusion in the evidence synthesis. A debriefing framework was used in all studies, mostly tailored to the study. Impact of the debrief was measured using satisfaction surveys (n=11) and/or participant performance (n=18). Three themes emerged from the data synthesis: selection and training of facilitators, debrief model and debrief assessment. There was little commonality across studies in terms of participants, experience of faculty and measures used.ConclusionsA range of debriefing frameworks were used in these studies. Some key aspects of debrief for team-based simulation, such as facilitator training, the inclusion of a reaction phase and the impact of learner characteristics on debrief outcomes, have no or limited evidence and provide opportunities for future research particularly with interprofessional groups.
QRISK3 improves detection of cardiovascular disease risk in patients with systemic lupus erythematosus
Authors: Edwards Nicola , Langford-Smith Alexander W W , Parker Benjamin J , Bruce Ian N , Reynolds John A , Alexander M Yvonne , McCarthy Eoghan M , Wilkinson Fiona L 
Published: August 2018

Objective10-year cardiovascular disease (CVD) risk scores are calculated using algorithms, including Framingham (worldwide) and QRISK2 (UK). Recently, an updated QRISK3 model was introduced, which considers new variables including SLE and steroid prescription, not included in QRISK2 and Framingham algorithms. We sought to determine the extent to which QRISK3 improves identification of high-risk patients with SLE and whether the score relates to standard and novel markers of SLE-specific endothelial dysfunction.MethodsFramingham and QRISK2/3 scores were calculated in patients with SLE (n=109) and healthy controls (n=29) using clinical measures. In a smaller cohort (n=58), markers of inflammation and endothelial dysfunction, including CD144+endothelial microvesicles (EMVs), triglycerides, vascular cell adhesion molecule (VCAM) and high-sensitivity C reactive protein (hsCRP) were quantified by flow cytometry and ELISA, respectively.ResultsPatients with SLE demonstrated significantly higher QRISK3 scores than controls (5.0%vs0.3%, p<0.001). 21/109 patients with SLE (19%) and 24/109(22%) were newly identified as being at high risk of a CV event when using QRISK3 versus QRISK2 (29vs8patients) and QRISK3 versus Framingham (29vs5patients; p<0.001), respectively. These ‘new QRISK3’ patients with SLE were more likely to have lupus nephritis, be anticardiolipin antibody positive, currently prescribed corticosteroids, had a higher Body Mass Index and systolic blood pressure (BP) than low-risk patients with SLE. Rates of antiplatelet (8/21) and statin use (5/21) were low in the new QRISK3 group. EMVs, hsCRP and triglyceride levels were significantly higher in new QRISK3 patientscompared with low-risk patients with SLE (p<0.05). Furthermore, pulse wave velocity and VCAM were significantly elevated in all high versus low QRISK3 patients.ConclusionsQRISK3 captures significantly more patients with SLE with an elevated 10-year risk of developing CVD, which is associated with measures of endothelial dysfunction; EMVs and systolic BP. The adoption of QRISK3 will enhance management of CVD risk in patients with SLE for improved outcome.
Efficient Race Detection for Reducer Hyperobjects
Authors: Lee I-Ting Angelina , Schardl Tao B. 
Published: August 2018

A multithreaded Cilk program that is ostensibly deterministic may nevertheless behave nondeterministically due to programming errors in the code. For a Cilk program that uses reducers—a general reduction mechanism supported in various Cilk dialects—such programming errors are especially challenging to debug, because the errors can expose the nondeterminism in how the Cilk runtime system manages reducers.
We identify two unique types of races that arise from incorrect use of reducers in a Cilk program, and we present two algorithms to catch these races. The first algorithm, called the Peer-Set algorithm, detects view-read races, which occur when the program attempts to retrieve a value out of a reducer when the read may result in a nondeterministic value, such as before all previously spawned subcomputations that might update the reducer have necessarily returned. The second algorithm, called the SP+ algorithm, detects determinacy races—instances where a write to a memory location occurs logically in parallel with another access to that location—even when the raced-on memory locations relate to reducers. Both algorithms are provably correct, asymptotically efficient, and can be implemented efficiently in practice. We have implemented both algorithms in our prototype race detector, Rader. When running Peer-Set, Rader incurs a geometric-mean multiplicative overhead of 2.56 over running the benchmark without instrumentation. When running SP+, Rader incurs a geometric-mean multiplicative overhead of 16.94.
Sonography of the optic nerve sheath diameter before and after microsurgical closure of a dural CSF fistula in patients with spontaneous intracranial hypotension – a consecutive cohort study
Authors: Fichtner Jens , Ulrich Christian T , Fung Christian , Cipriani Debora , Gralla Jan , Piechowiak Eike Immo , Schlachetzki Felix , Z'Graggen Werner J , Raabe Andreas , Beck Jürgen 
Published: August 2018

Objective Spontaneous intracranial hypotension is caused by spinal cerebrospinal fluid leakage. Patients with orthostatic headaches and cerebrospinal fluid leakage show a decrease in optic nerve sheath diameter upon movement from supine to upright position. We hypothesized that the decrease in optic nerve sheath diameter upon gravitational challenge would cease after closure of the leak. Methods We included 29 patients with spontaneous intracranial hypotension and refractory symptoms admitted from 2013 to 2016. The systematic workup included: Optic nerve sheath diameter sonography, spinal MRI and dynamic myelography with subsequent CT. Microsurgical sealing of the cerebrospinal fluid leak was the aim in all cases. Results Of 29 patients with a proven cerebrospinal fluid leak, one declined surgery. A single patient was lost to follow-up. In 27 cases, the cerebrospinal fluid leak was successfully sealed by microsurgery. The width of the optic nerve sheath diameter in supine position increased from 5.08 ± 0.66 mm before to 5.36 ± 0.53 mm after surgery ( p = 0.03). Comparing the response of the optic nerve sheath diameter to gravitational challenge, there was a significant change from before (−0.36 ± 0.32 mm) to after surgery (0.00 ± 0.19 mm, p < 0.01). In parallel, spontaneous intracranial hypotension-related symptoms resolved in 26, decreased in one and persisted in a single patient despite recovery of gait. Conclusions The sonographic assessment of the optic nerve sheath diameter with gravitational challenge can distinguish open from closed spinal cerebrospinal fluid fistulas in spontaneous intracranial hypotension patients. A response to the gravitational challenge, that is, no more collapse of the optic nerve sheath while standing up, can be seen after successful treatment and correlates with the resolution of clinical symptoms. Sonography of the optic nerve sheath diameter may be utilized for non-invasive follow-up in spontaneous intracranial hypotension.
Cyclic changes in sensations to painful stimuli in migraine patients
Authors: Strupf Marion , Fraunberger Britta , Messlinger Karl , Namer Barbara 
Published: August 2018

Introduction Migraine is characterized by cycling phases (interictal, preictal, ictal and postictal) with differing symptoms, while in chronic tension type headache pain phases are fluctuating. The question we asked is whether these phases are associated with changes in parameters of somatosensation and axon-reflex erythema. Methods Patients with episodic migraine and chronic tension type headache were examined psychophysically in the interictal, preictal and ictal phase and healthy subjects on five different test days. Thresholds and suprathreshold ratings of pressure and electrical pain were assessed on three different regions of the head. In migraine patients and in healthy controls, electrically induced axon-reflex erythema was measured in the area of the first trigeminal branch. All migraine patients filled out questionnaires about prodromal symptoms at every visit. Results The axon-reflex erythema was always larger in patients with migraine in contrast to healthy subjects. The pressure pain threshold was lower in migraine patients and chronic tension type headache in comparison to healthy subjects. Electrical pain thresholds did not differ between headache patients and healthy subjects and showed no changes between the phases. However, suprathreshold pain ratings showed less habituation solely in the preictal phase of migraine. The number of prodromal symptoms in migraine patients was increased in the preictal and ictal phase. Discussion Reduced habituation was the unique sign of the preictal phase in migraine patients, independently of prodromal symptoms, whereas a larger axon-reflex erythema and higher pressure pain sensitivity are constitutional and non-phase dependent properties of migraine. Reduced inhibitory mechanisms in the preictal phase may contribute to trigger headache attacks in migraine.
Referral for first glaucoma surgery in Europe, the ReF-GS study
Authors: Holló Gábor , Schmidl Doreen , Hommer Anton 
Published: August 2018

Purpose: To analyze the appropriateness of referrals for incisional glaucoma-surgery in Europe. Methods: Referrals for the first open-angle glaucoma surgery between January and October 2017 were analyzed in 18 countries: 8 “old” European Union, 7 “new” European Union and 3 non-European Union European countries. Results: Most eyes had primary open-angle or exfoliative glaucoma. The average mean deviation was −13.8 dB with split fixation in 44.3%. No structural progression analysis was made before the referrals. The most common medications were the combination of a prostaglandin analog, timolol and a carbonic anhydrase inhibitor (30.0%), and all other combinations comprising ⩾ 3 molecules (33.8%). Laser trabeculoplasty was reported in only 18.4%. Of the 294 referrals, 41.5% were appropriate and timely, 35.0% appropriate but later than optimal, and 17.6% appropriate but too late (minimal vision maintained). The treatment period was significantly longer (median: 7 years) in the “old” European Union countries than in the other groups (3 and 2 years, respectively). No between-group differences were seen in intraocular pressure and mean deviation, but the non-European Union group referred the patients at significantly lower cup/disk ratio and eye drop usage than the other groups. Split fixation was significantly more common in the “old” (60.6%) than the “new” European Union countries (38.7%), and in both EU country-groups than in the non-European Union countries (13.6%). Conclusions: Of 294 European open-angle glaucoma referrals for first glaucoma-surgery, 41.5% were completely satisfactory. The damage was typically advanced, and the care varied considerably among the countries. This suggests that further efforts are necessary to improve glaucoma care in Europe.
Detection and interpretation of fecal host mRNA in rural Malawian infants aged 6–12 months at risk for environmental enteric dysfunction
Authors: Ordiz M Isabel , Wold Karl , Kaimila Yankho , Divala Oscar , Gilstrap Madeline , Lu Henry Z , Manary Mark J 
Published: August 2018

Recent studies have suggested that environmental enteric dysfunction can be assessed in rural African children by measuring levels of fecal mRNA transcripts. The field collection of fecal samples is less invasive and cumbersome than administration of the lactulose:mannitol test, which is typically used to assess environmental enteric dysfunction. This study sought to determine if, as in children aged 12–60 months, an array of seven fecal host transcripts (CD53, CDX1, HLA-DRA, TNF, S100A8, MUC12, and REG1A) could predict environmental enteric dysfunction in rural African infants. Host fecal transcript abundance was correlated to the percentage of lactulose (%L) excreted in the urine for 340 samples from Malawian children aged 6–12 months. Permeability was categorized as not severe (%L < 0.45) and severe (%L ≥ 0.45). This study found the prevalence of severe environmental enteric dysfunction to be 114/834 (14%), lower than what was previously reported for 12–60 months old children, 595/1521 (39%, P = 0.001). In linear regression analysis with the seven host transcripts, two were associated with %L: β coefficients of −1.843 ( P = 0.035) and 0.215 ( P = 0.006) for CDX1 and REG1A, respectively. The seven fecal host transcripts in a random forest model did not predict severe environmental enteric dysfunction. Future models utilizing different transcripts identified from an untargeted, agnostic assessment of all potential host transcripts could provide accurate predictions of environmental enteric dysfunction in infants. Impact statement Environmental enteric dysfunction (EED) is associated with reduced linear growth. The dual sugar absorption test has been used as a non-invasive method to determine the gut health of individuals. Alternative methods using fecal host mRNAs as predictors of the gut health are promising. In older children, we have determined that seven transcripts can predict the gut health in a random forest model. Our current study determined that the host fecal mRNA is abundant in infants and toddlers alike. Severe EED in rural Malawian children is less prevalent in infants than in young children. REG1A and CDX1 are associated with gut health. Fecal host mRNA may well be a means to assess gut health in African infants, but the panel of transcripts used to do this will differ from that in older children.