bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and Molecular Basis for Resistance to Aminoglycoside Antibiotics by the Adenylyltransferase ANT(2″)-Ia
Authors: Cox Georgina , Stogios Peter J. , Savchenko Alexei , Wright Gerard D. 
Published: January 2015

ABSTRACT

The aminoglycosides are highly effective broad-spectrum antimicrobial agents. However, their efficacy is diminished due to enzyme-mediated covalent modification, which reduces affinity of the drug for the target ribosome. One of the most prevalent aminoglycoside resistance enzymes in Gram-negative pathogens is the adenylyltransferase ANT(2″)-Ia, which confers resistance to gentamicin, tobramycin, and kanamycin. Despite the importance of this enzyme in drug resistance, its structure and molecular mechanism have been elusive. This study describes the structural and mechanistic basis for adenylylation of aminoglycosides by the ANT(2″)-Ia enzyme. ANT(2″)-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2″-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core. The catalyzed reaction follows a direct AMP transfer mechanism from ATP to the substrate antibiotic. Central to catalysis is the coordination of two Mg
2+
ions, positioning of the modifiable substrate ring, and the presence of a catalytic base (Asp
86
). Comparative structural analysis revealed that ANT(2″)-Ia has a two-domain structure with an N-terminal active-site architecture that is conserved among other antibiotic nucleotidyltransferases, including Lnu(A), LinB, ANT(4′)-Ia, ANT(4″)-Ib, and ANT(6)-Ia. There is also similarity between the nucleotidyltransferase fold of ANT(2″)-Ia and DNA polymerase β. This similarity is consistent with evolution from a common ancestor, with the nucleotidyltransferase fold having adapted for activity against chemically distinct molecules.

IMPORTANCE
To successfully manage the threat associated with multidrug-resistant infectious diseases, innovative therapeutic strategies need to be developed. One such approach involves the enhancement or potentiation of existing antibiotics against resistant strains of bacteria. The reduction in clinical usefulness of the aminoglycosides is a particular problem among Gram-negative human pathogens, since there are very few therapeutic options for infections caused by these organisms. In order to successfully circumvent or inhibit the activity of aminoglycoside-modifying enzymes, and to thus rejuvenate the activity of the aminoglycoside antibiotics against Gram-negative pathogens, structural and mechanistic information is crucial. This study reveals the structure of a clinically prevalent aminoglycoside resistance enzyme [ANT(2″)-Ia] and depicts the molecular basis underlying modification of antibiotic substrates. Combined, these findings provide the groundwork for the development of broad-spectrum inhibitors against antibiotic nucleotidyltransferases.
Protein A Suppresses Immune Responses during Staphylococcus aureus Bloodstream Infection in Guinea Pigs
Authors: Kim Hwan Keun , Falugi Fabiana , Thomer Lena , Missiakas Dominique M. , Schneewind Olaf 
Published: January 2015

ABSTRACT  Staphylococcus aureusinfection is not associated with the development of protective immunity, and disease relapses occur frequently. We hypothesize that protein A, a factor that binds immunoglobulin Fcγ and cross-links VH3 clan B cell receptors (IgM), is the staphylococcal determinant for host immune suppression. To test this, vertebrate IgM was examined for protein A cross-linking. High VH3 binding activity occurred with human and guinea immunoglobulin, whereas mouse and rabbit immunoglobulins displayed little and no binding, respectively. Establishing a guinea pig model of S. aureus bloodstream infection, we show that protein A functions as a virulence determinant and suppresses host B cell responses. Immunization with SpAKKAA, which cannot bind immunoglobulin, elicits neutralizing antibodies that enable guinea pigs to develop protective immunity.IMPORTANCE Staphylococcus aureusis the leading cause of soft tissue and bloodstream infections; however, a vaccine with clinical efficacy is not available. Using mice to model staphylococcal infection, earlier work identified protective antigens; however, corresponding human clinical trials did not reach their endpoints. We show that B cell receptor (IgM) cross-linking by protein A is an important immune evasion strategy of S. aureus that can be monitored in a guinea pig model of bloodstream infection. Further, immunization with nontoxigenic protein A enables infected guinea pigs to elicit antibody responses that are protective against S. aureus. Thus, the guinea pig model may support preclinical development of staphylococcal vaccines.
Sputum eosinophilia is a determinant of FEV1 decline in occupational asthma: results of an observational study
Authors: Talini Donatella , Novelli Federica , Bacci Elena , Bartoli Marialaura , Cianchetti Silvana , Costa Francesco , Dente Federico L , Di Franco Antonella , Latorre Manuela , Malagrinò Laura , Vagaggini Barbara , Celi Alessandro , Paggiaro Pierluigi 
Published: January 2015

ObjectiveTo evaluate the potential determinants of forced expiratory volume in 1 s (FEV1) decline in workers with occupational asthma (OA) still exposed to the causative agent. We hypothesised that sputum eosinophilia might be a predictor of poor asthma outcome after diagnosis.Setting, design and participantsIn a specialistic clinical centre of the University Hospital of Pisa, we studied 39 participants (28 M, 11 F) diagnosed as having OA, routinely followed up between 1990 and 2009. They were a subgroup of 94 participants diagnosed as affected by OA in that period: 9 had been removed from work at the diagnosis, 21 were excluded for having ceased occupational exposure after few months from diagnosis, and 25 were lost at the follow-up or had no acceptable sputum measurements at the diagnosis. Estimates of the decline in FEV1 were obtained by means of simple regression analysis during the period of occupational exposure after diagnosis. Logistic regression was used to analyse the effects of factors (baseline FEV1 and sputum inflammatory cells, duration and type of exposure) that may potentially influence FEV1 decline.ResultsAt follow-up (5.7+3.7 years), most participants were still symptomatic despite inhaled corticosteroids (ICS) treatment and had their occupational exposure reduced. Participants with higher sputum eosinophils (>3%) at baseline had a significantly greater decline of FEV1 (–52.5 vs −18.6 mL/year, p=0.012). Logistic regression showed that persistent exposure and sputum eosinophilia were significantly associated with a greater decline in FEV1 (OR 11.5, 95% CI 1.8 to 71.4, p=0.009 and OR 6.7, 95% CI 1.1 to 41.7, p= 0.042, respectively).ConclusionsSputum eosinophilia at diagnosis, together with the persistence of occupational exposure during follow-up, may contribute to a greater decline in FEV1 in patients with OA still at work. Further long-term studies are required as to whether intensive ICS treatment may be beneficial for patients with OA and increase ad eosinophilic inflammation.
Healthcare professionals’ perceptions of clinical governance implementation: a qualitative New Zealand study of 3205 open-ended survey comments
Authors: Gauld Robin , Horsburgh Simon 
Published: January 2015

ObjectivesTo investigate healthcare professional perceptions of local implementation of a national clinical governance policy in New Zealand.DesignRespondent comments written at the end of a national healthcare professional survey designed to assess implementation of core components of the clinical governance policy.SettingThe written comments were provided by respondents to a survey distributed to over 41 000 registered healthcare professionals employed in 19 of New Zealand's government-funded District Health Boards. Comments were analysed and categorised within emerging themes.Results3205 written comments were received. Five key themes illustrating barriers to clinical governance implementation were found, representing problems with: developing management–clinical relations; clinicians stepping up into clinical governance and leadership activities; interprofessional relations; training needs for governance and leadership; and having insufficient time to get involved.ConclusionsDespite a national policy on clinical governance which New Zealand's government launched in 2009, this study found that considerable effort is required to build clinical governance at the local level. This finding parallels with other studies in the field. Two areas demand attention: building systems for organisational governance and leadership; and building professional governance arrangements.
Systematic review of mental health and well-being outcomes following community-based obesity prevention interventions among adolescents
Authors: Hoare Erin , Fuller-Tyszkiewicz Matthew , Skouteris Helen , Millar Lynne , Nichols Melanie , Allender Steven 
Published: January 2015

ObjectivesThis paper aimed to systematically evaluate the mental health and well-being outcomes observed in previous community-based obesity prevention interventions in adolescent populations.SettingSystematic review of literature from database inception to October 2014. Articles were sourced from CINAHL, Global Health, Health Source: Nursing and Academic Edition, MEDLINE, PsycARTICLES and PsycINFO, all of which were accessed through EBSCOhost. The Cochrane Database was also searched to identify all eligible articles. PRISMA guidelines were followed and search terms and search strategy ensured all possible studies were identified for review.ParticipantsIntervention studies were eligible for inclusion if they were: focused on overweight or obesity prevention, community-based, targeted adolescents (aged 10–19 years), reported a mental health or well-being measure, and included a comparison or control group. Studies that focused on specific adolescent groups or were treatment interventions were excluded from review. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines.Primary and secondary outcome measuresPrimary outcomes were measures of mental health and well-being, including diagnostic and symptomatic measures. Secondary outcomes included adiposity or weight-related measures.ResultsSeven studies met the inclusion criteria; one reported anxiety/depressive outcomes, two reported on self-perception well-being measures such as self-esteem and self-efficacy, and four studies reported outcomes of quality of life. Positive mental health outcomes demonstrated that following obesity prevention, interventions included a decrease in anxiety and improved health-related quality of life. Quality of evidence was graded as very low.ConclusionsAlthough positive outcomes for mental health and well-being do exist, controlled evaluations of community-based obesity prevention interventions have not often included mental health measures (n=7). It is recommended that future interventions incorporate mental health and well-being measures to identify any potential mechanisms influencing adolescent weight-related outcomes, and equally to ensure interventions are not causing harm to adolescent mental health.
Primary bacteraemia is associated with a higher mortality risk compared with pulmonary and intra-abdominal infections in patients with sepsis: a prospective observational cohort study
Authors: Mansur Ashham , Klee Yvonne , Popov Aron Frederik , Erlenwein Joachim , Ghadimi Michael , Beissbarth Tim , Bauer Martin , Hinz José 
Published: January 2015

ObjectiveTo investigate whether common infection foci (pulmonary, intra-abdominal and primary bacteraemia) are associated with variations in mortality risk in patients with sepsis.DesignProspective, observational cohort study.SettingThree surgical intensive care units (ICUs) at a university medical centre.ParticipantsA total of 327 adult Caucasian patients with sepsis originating from pulmonary, intra-abdominal and primary bacteraemia participated in this study.Primary and secondary outcome measuresThe patients were followed for 90 days and mortality risk was recorded as the primary outcome variable. To monitor organ failure, sepsis-related organ failure assessment (Sequential Organ Failure Assessment, SOFA) scores were evaluated at the onset of sepsis and throughout the observational period as secondary outcome variables.ResultsA total of 327 critically ill patients with sepsis were enrolled in this study. Kaplan-Meier survival analysis showed that the 90-day mortality risk was significantly higher among patients with primary bacteraemia than among those with pulmonary and intra-abdominal foci (58%, 35% and 32%, respectively; p=0.0208). To exclude the effects of several baseline variables, we performed multivariate Cox regression analysis. Primary bacteraemia remained a significant covariate for mortality in the multivariate analysis (HR 2.10; 95% CI 1.14 to 3.86; p=0.0166). During their stay in the ICU, the patients with primary bacteraemia presented significantly higher SOFA scores than those of the patients with pulmonary and intra-abdominal infection foci (8.5±4.7, 7.3±3.4 and 5.8±3.5, respectively). Patients with primary bacteraemia presented higher SOFA-renal score compared with the patients with other infection foci (1.6±1.4, 0.8±1.1 and 0.7±1.0, respectively); the patients with primary bacteraemia required significantly more renal replacement therapy than the patients in the other groups (29%, 11% and 12%, respectively).ConclusionsThese results indicate that patients with sepsis with primary bacteraemia present a higher mortality risk compared with patients with sepsis of pulmonary or intra-abdominal origins. These results should be assessed in patients with sepsis in larger, independent cohorts.
Prevalence of tinnitus and/or hyperacusis in children and adolescents: study protocol for a systematic review
Authors: Nemholt Susanne Steen , Schmidt Jesper Hvass , Wedderkopp Niels , Baguley David M 
Published: January 2015

IntroductionThere is some debate as to what extent epidemiological data for the prevalence of childhood tinnitus can be relied on. While indications are that the prevalence is relatively high, referral numbers for children with tinnitus are reported to be low and many of the studies have a number of methodological difficulties. We describe the protocol of a systematic review aimed at assessing the prevalence of tinnitus and/or hyperacusis in children and young people.Methods and analysisWe will include studies of any design (except case reports or case series) comparing the prevalence of tinnitus and/or hyperacusis in children and young people with and without hearing loss, any known external exposure and psychological disorders. We will search the following databases: PubMed, EMBASE and Scopus. No restrictions of language will be applied in the search strategy but during the article selection language is limited to English, German and Scandinavian languages. Primary and additional outcomes will be the prevalence of tinnitus/hyperacusis and the severity, respectively.Ethics and disseminationNo ethical issues are foreseen. The results will be published in a peer-reviewed journal and presented at national and international conferences of audiology and paediatrics.Trail registration numberThis review protocol is registered in the PROSPERO International Prospective Register of Systematic Reviews, registration number CRD42014013456.
Severity of urban cycling injuries and the relationship with personal, trip, route and crash characteristics: analyses using four severity metrics
Authors: Cripton Peter A , Shen Hui , Brubacher Jeff R , Chipman Mary , Friedman Steven M , Harris M Anne , Winters Meghan , Reynolds Conor C O , Cusimano Michael D , Babul Shelina , Teschke Kay 
Published: January 2015

ObjectiveTo examine the relationship between cycling injury severity and personal, trip, route and crash characteristics.MethodsData from a previous study of injury risk, conducted in Toronto and Vancouver, Canada, were used to classify injury severity using four metrics: (1) did not continue trip by bike; (2) transported to hospital by ambulance; (3) admitted to hospital; and (4) Canadian Triage and Acuity Scale (CTAS). Multiple logistic regression was used to examine associations with personal, trip, route and crash characteristics.ResultsOf 683 adults injured while cycling, 528 did not continue their trip by bike, 251 were transported by ambulance and 60 were admitted to hospital for further treatment. Treatment urgencies included 75 as CTAS=1 or 2 (most medically urgent), 284 as CTAS=3, and 320 as CTAS=4 or 5 (least medically urgent). Older age and collision with a motor vehicle were consistently associated with increased severity in all four metrics and statistically significant in three each (both variables with ambulance transport and CTAS; age with hospital admission; and motor vehicle collision with did not continue by bike). Other factors were consistently associated with more severe injuries, but statistically significant in one metric each: downhill grades; higher motor vehicle speeds; sidewalks (these significant for ambulance transport); multiuse paths and local streets (both significant for hospital admission).ConclusionsIn two of Canada's largest cities, about one-third of the bicycle crashes were collisions with motor vehicles and the resulting injuries were more severe than in other crash circumstances, underscoring the importance of separating cyclists from motor vehicle traffic. Our results also suggest that bicycling injury severity and injury risk would be reduced on facilities that minimise slopes, have lower vehicle speeds, and that are designed for bicycling rather than shared with pedestrians.
Perception and use of massive open online courses among medical students in a developing country: multicentre cross-sectional study
Authors: Aboshady Omar A , Radwan Ahmed E , Eltaweel Asmaa R , Azzam Ahmed , Aboelnaga Amr A , Hashem Heba A , Darwish Salma Y , Salah Rehab , Kotb Omar N , Afifi Ahmed M , Noaman Aya M , Salem Dalal S , Hassouna Ahmed 
Published: January 2015

ObjectivesTo assess the prevalence of awareness and use of massive open online courses (MOOCs) among medical undergraduates in Egypt as a developing country, as well as identifying the limitations and satisfaction of using these courses.DesignA multicentre, cross-sectional study using a web-based, pilot-tested and self-administered questionnaire.SettingsTen out of 19 randomly selected medical schools in Egypt.Participants2700 undergraduate medical students were randomly selected, with an equal allocation of participants in each university and each study year.Primary and secondary outcome measuresPrimary outcome measures were the percentages of students who knew about MOOCs, students who enrolled and students who obtained a certificate. Secondary outcome measures included the limitations and satisfaction of using MOOCs through five-point Likert scale questions.ResultsOf 2527 eligible students, 2106 completed the questionnaire (response rate 83.3%). Of these students, 456 (21.7%) knew the term MOOCs or websites providing these courses. Out of the latter, 136 (29.8%) students had enrolled in at least one course, but only 25 (18.4%) had completed courses earning certificates. Clinical year students showed significantly higher rates of knowledge (p=0.009) and enrolment (p<0.001) than academic year students. The primary reasons for the failure of completion of courses included lack of time (105; 77.2%) and slow Internet speed (73; 53.7%). Regarding the 25 students who completed courses, 21 (84%) were satisfied with the overall experience. However, there was less satisfaction regarding student–instructor (8; 32%) and student–student (5; 20%) interactions.ConclusionsAbout one-fifth of Egyptian medical undergraduates have heard about MOOCs with only about 6.5% actively enrolled in courses. Students who actively participated showed a positive attitude towards the experience, but better time-management skills and faster Internet connection speeds are required. Further studies are needed to survey the enrolled students for a better understanding of their experience.
Real-time patterns of smoking and alcohol use: an observational study protocol of risky-drinking smokers
Authors: Cohn Amy , Brandon Thomas , Armeli Stephen , Ehlke Sarah , Bowers Molly 
Published: January 2015

IntroductionDespite the strong relationship between smoking and health-related consequences, very few smokers quit. Heavy drinking is a significant risk factor for health consequences, and is implicated in persistent smoking and less success at quitting smoking. Self-efficacy (SE) to abstain from smoking is an important determinant of smoking outcomes and may link alcohol use to poor quit rates. Even though research has demonstrated a strong association between drinking and smoking, and the multiplicative effect of these substances on cancer-related, heavy-drinking smokers has been largely ignored in the literature. Further, research has not taken advantage of innovative methods, such as ecological momentary assessment, to capture the impact of daily factors on smoking cessation outcomes in this particular group. The proposed study identifies daily changing factors that impede or promote SE and future smoking cessation efforts in risky-drinking smokers.Methods and analysisThis is an observational study of 84 regular smokers (≥10 cigarettes per day) who drink at risky levels, report a desire to quit in the next 6 months, and show no evidence of psychiatric disturbance, severe history of alcohol withdrawal or drug dependence (excluding nicotine and caffeine). Participants report on their smoking, alcohol consumption and SE related to smoking twice a day for 28 days using interactive voice response (IVR) surveys. Multilevel regression and path models will examine within-person daily associations among drinking, smoking and SE, and how these variables predict the likelihood of future smoking behaviour at 1 and 6 months follow-up.Ethics and disseminationThis protocol was approved by an accredited Institutional Review Board. The findings will help us understand the factors that promote or impede smoking cessation among a high-risk group of smokers (heavy-drinking smokers) and will be disseminated through peer-reviewed journal articles and presentations at national conferences.