516 research outputs found
Conserved Endonuclease Function of Hantavirus L Polymerase.
Hantaviruses are important emerging pathogens belonging to the Bunyaviridae family. Like other segmented negative strand RNA viruses, the RNA-dependent RNA polymerase (RdRp) also known as L protein of hantaviruses lacks an intrinsic "capping activity". Hantaviruses therefore employ a "cap snatching" strategy acquiring short 5' RNA sequences bearing 5'cap structures by endonucleolytic cleavage from host cell transcripts. The viral endonuclease activity implicated in cap snatching of hantaviruses has been mapped to the N-terminal domain of the L protein. Using a combination of molecular modeling and structure-function analysis we confirm and extend these findings providing evidence for high conservation of the L endonuclease between Old and New World hantaviruses. Recombinant hantavirus L endonuclease showed catalytic activity and a defined cation preference shared by other viral endonucleases. Based on the previously reported remarkably high activity of hantavirus L endonuclease, we established a cell-based assay for the hantavirus endonuclase function. The robustness of the assay and its high-throughput compatible format makes it suitable for small molecule drug screens to identify novel inhibitors of hantavirus endonuclease. Based on the high degree of similarity to RdRp endonucleases, some candidate inhibitors may be broadly active against hantaviruses and other emerging human pathogenic Bunyaviruses
Characteristics differentiating problem representation synthesis between novices and experts
Background: Formulating a thoughtful problem representation (PR) is fundamental to sound clinical reasoning and an essential component of medical education. Aside from basic structural recommendations, little consensus exists on what characterizes high-quality PRs. Objectives: To elucidate characteristics that distinguish PRs created by experts and novices. Methods: Early internal medicine residents (novices) and inpatient teaching faculty (experts) from two academic medical centers were given two written clinical vignettes and were instructed to write a PR and three-item differential diagnosis for each. Deductive content analysis described the characteristics comprising PRs. An initial codebook of characteristics was refined iteratively. The primary outcome was differences in characteristic frequencies between groups. The secondary outcome was characteristics correlating with diagnostic accuracy. Mixed-effects regression with random effects modeling compared case-level outcomes by group. Results: Overall, 167 PRs were analyzed from 30 novices and 54 experts. Experts included 0.8 fewer comorbidities (p <.01) and 0.6 more examination findings (p =.01) than novices on average. Experts were less likely to include irrelevant comorbidities (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2ā0.8) or a diagnosis (OR = 0.3, 95%Ā CI = 0.1ā0.8) compared with novices. Experts encapsulated clinical data into higher-order terms (e.g., sepsis) than novices (p <.01) while including similar numbers of semantic qualifiers (SQs). Regardless of expertise level, PRs following a three-part structure (e.g., demographics, temporal course, and clinical syndrome) and including temporal SQs were associated with diagnostic accuracy (p <.01). Conclusions: Compared with novices, expert PRs include less irrelevant data and synthesize information into higher-order concepts. Future studies should determine whether targeted educational interventions for PRs improve diagnostic accuracy.</p
Characteristics differentiating problem representation synthesis between novices and experts
Background: Formulating a thoughtful problem representation (PR) is fundamental to sound clinical reasoning and an essential component of medical education. Aside from basic structural recommendations, little consensus exists on what characterizes high-quality PRs. Objectives: To elucidate characteristics that distinguish PRs created by experts and novices. Methods: Early internal medicine residents (novices) and inpatient teaching faculty (experts) from two academic medical centers were given two written clinical vignettes and were instructed to write a PR and three-item differential diagnosis for each. Deductive content analysis described the characteristics comprising PRs. An initial codebook of characteristics was refined iteratively. The primary outcome was differences in characteristic frequencies between groups. The secondary outcome was characteristics correlating with diagnostic accuracy. Mixed-effects regression with random effects modeling compared case-level outcomes by group. Results: Overall, 167 PRs were analyzed from 30 novices and 54 experts. Experts included 0.8 fewer comorbidities (p <.01) and 0.6 more examination findings (p =.01) than novices on average. Experts were less likely to include irrelevant comorbidities (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2ā0.8) or a diagnosis (OR = 0.3, 95%Ā CI = 0.1ā0.8) compared with novices. Experts encapsulated clinical data into higher-order terms (e.g., sepsis) than novices (p <.01) while including similar numbers of semantic qualifiers (SQs). Regardless of expertise level, PRs following a three-part structure (e.g., demographics, temporal course, and clinical syndrome) and including temporal SQs were associated with diagnostic accuracy (p <.01). Conclusions: Compared with novices, expert PRs include less irrelevant data and synthesize information into higher-order concepts. Future studies should determine whether targeted educational interventions for PRs improve diagnostic accuracy.</p
Assessment of daily profiles of ADHD and ODD symptoms, and symptomatology related to ADHD medication, by parent and teacher ratings
DAYAS is a new two-part rating scale that assesses: (1) ADHD and ODD symptoms (externalising symptom ratings) and (2) symptomatology potentially related to ADHD medication (potentially medication-related symptoms) in real-world settings at different time periods throughout a normal school day. Data from a proof-of-concept study and two observational trials (MedikinetĀ® retard [methylphenidate] and the Equasym XLĀ® [methylphenidate] OBSEER study) evaluated: (1) validity of weekly externalising symptom ratings using DAYAS, in place of daily ratings; (2) reliability and internal consistency of DAYAS ratings for externalising symptoms and potentially medication-related symptoms; and (3) convergent and divergent validity of the externalising symptom ratings with existing validated scales. From the proof-of-concept study, daily scores by period of day and during the whole day correlated strongly with equivalent weekly scores (rĀ =Ā 0.83ā0.92). Internal consistency of externalising symptom rating scales calculated from pooled data were acceptable or good by period of day (Cronbachās alphaĀ =Ā 0.68ā0.90) and very high for whole day scores (Cronbachās alphaĀ =Ā 0.88ā0.95). Internal consistency of the rating scale for potentially medication-related symptoms was also good for both teacher and parent ratings. From OBSEER data, correlations between FBB-ADHD total symptom scores and ratings on both parent and teacher versions of DAYAS were high (rĀ =Ā 0.73 and rĀ =Ā 0.84, respectively). Correlations between DAYAS and SDQ were highest for the SDQ subscales hyperactivity and conduct problems and substantially lower for pro-social behaviour, peers and emotional problems. The DAYAS rating scale had good internal consistency, and DAYAS scores correlated well with existing validated scales and the SDQ subscales hyperactivity and conduct problems. Weekly DAYAS scores (whole day and by period of day) could be considered a suitable replacement for daily assessment scores
Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study.
BACKGROUND: The recombinant vesicular stomatitis virus (rVSV) vaccine expressing the Zaire Ebola virus (ZEBOV) glycoprotein is efficacious in the weeks following single-dose injection, but duration of immunity is unknown. We aimed to assess antibody persistence at 1 and 2 years in volunteers who received single-dose rVSV-ZEBOV in three previous trials. METHODS: In this observational cohort study, we prospectively followed-up participants from the African and European phase 1 rVSV-ZEBOV trials, who were vaccinated once in 2014-15 with 300ā000 (low dose) or 10-50 million (high dose) plaque-forming units (pfu) of rVSV-ZEBOV vaccine to assess ZEBOV glycoprotein (IgG) antibody persistence. The primary outcome was ZEBOV glycoprotein-specific IgG geometric mean concentrations (GMCs) measured yearly by ELISA compared with 1 month (ie, 28 days) after immunisation. We report GMCs up to 2 years (Geneva, Switzerland, including neutralising antibodies up to 6 months) and 1 year (LambarĆ©nĆ©, Gabon; Kilifi, Kenya) after vaccination and factors associated with higher antibody persistence beyond 6 months, according to multivariable analyses. Trials and the observational study were registered at ClinicalTrials.gov (Geneva: NCT02287480 and NCT02933931; Kilifi: NCT02296983) and the Pan-African Clinical Trials Registry (LambarĆ©nĆ© PACTR201411000919191). FINDINGS: Of 217 vaccinees from the original studies (102 from the Geneva study, 75 from the LambarĆ©nĆ© study, and 40 from the Kilifi study), 197 returned and provided samples at 1 year (95 from the Geneva study, 63 from the LambarĆ©nĆ©, and 39 from the Kilifi study) and 90 at 2 years (all from the Geneva study). In the Geneva group, 44 (100%) of 44 participants who had been given a high dose (ie, 10-50 million pfu) of vaccine and who were seropositive at day 28 remained seropositive at 2 years, whereas 33 (89%) of 37 who had been given the low dose (ie, 300ā000 pfu) remained seropositive for 2 years (p=0Ā·042). In participants who had received a high dose, ZEBOV glycoprotein IgG GMCs decreased significantly between their peak (at 1-3 months) and month 6 after vaccination in Geneva (p0Ā·05). Neutralising antibodies seem to be less durable, with seropositivity dropping from 64-71% at 28 days to 27-31% at 6 months in participants from the Geneva study. INTERPRETATION: Antibody responses to single-dose rVSV-ZEBOV vaccination are sustained across dose ranges and settings, a key criterion in countries where booster vaccinations would be impractical. FUNDING: The Wellcome Trust and Innovative Medicines Initiative 2 Joint Undertaking
Color perception deficits in co-existing attention-deficit/hyperactivity disorder and chronic tic disorders
Preliminary findings suggest that color perception, particularly of blue-yellow stimuli, is impaired in attention-deficit/hyperactivity disorder (ADHD) as well as in chronic tic disorders (CTD). However, these findings have been not replicated and it is unclear what these deficits mean for the comorbidity of ADHD + CTD. Four groups (ADHD, CTD, ADHD + CTD, controls) of children with similar age, IQ and gender distribution were investigated with the Farnsworth-Munsell 100 Hue Test (FMT) and the Stroop-Color-Word Task using a factorial design. Color perception deficits, as indexed by the FMT, were found for both main factors (ADHD and CTD), but there were no interaction effects. A preponderance of deficits on the blue-yellow compared to the red-green axis was detected for ADHD. In the Stroop task only the 'pure' ADHD group showed impairments in interference control and other parameters of Stroop performance. No significant correlations between any FMT parameter and color naming in the Stroop task were found. Basic color perception deficits in both ADHD and CTD could be found. Beyond that, it could be shown that these deficits are additive in the case of comorbidity (ADHD + CTD). Performance deficits on the Stroop task were present only in the 'pure' ADHD group. Hence, the latter may be compensated in the comorbid group by good prefrontal capabilities of CTD. The influence of color perception deficits on Stroop task performance might be negligible. Ā© 2007 Springer-Verlag
Editorial: Observational studies in ADHD: the effects of switching to modified-release methylphenidate preparations on clinical outcomes and adherence
Patients with ADHD may have better adherence to treatment with modified-release methylphenidate (MPH-MR) formulations, which are taken once daily, compared with immediate-release (IR) formulations, which need to be taken several times a day. Data on long-term outcomes such as adherence may be lacking from randomised controlled trials as these are usually only short-term. Observational studies, if performed and reported appropriately, can provide valuable long-term data on such outcomes, as well as additional information on effectiveness and efficiency, from a real-life setting. By reviewing previous observational studies that have investigated switching treatment from MPH-IR to MPH-MR, results from a new, naturalistic observational study, the OBSEER study, are put into context. We conclude that, based on observational trial data, switching from MPH-IR to MPH-MR is a valid clinical approach, with the potential for improved clinical outcome and treatment adherence
Formation of artificial pores in nano-TiO2 photo-electrode films using acetylene-black for high-efficiency, dye-sensitized solar cells
Acetylene-black paste without a light scattering layer was applied to meso-porous TiO2 photo-electrode films with a crystalline framework, a low residual carbon, and a tunable morphological pore size. The thermal-treated TiO2 photo-electrode films had an increased acetylene-black concentration with an increase in artificial pores and a decrease in residual carbon. The performance of dye-sensitized solar cells (DSSCs) was enhanced by the use of the TiO2 photo-anode pastes at various acetylene-black concentrations. The photo-conversion efficiency of the DSSCs using TiO2 photo-electrode films with 1.5 wt% acetylene-black was enhanced from 7.98 (no acetylene-black) to 9.75% without the integration of a light-scattering layer.open5
An observational study of once-daily modified-release methylphenidate in ADHD: effectiveness on symptoms and impairment, and safety
ADHD affects over 5% of children worldwide. It is typically treated with stimulant medications, and methylphenidate (MPH) is the most commonly prescribed. This study investigated the effectiveness, on symptoms and impairment, and safety of Equasym XLĀ®, a combination of 30% immediate-release and 70% modified-release MPH, in the treatment of ADHD in daily clinical practice. This open-label, observational, post-marketing surveillance study was conducted in 169 centres in Germany. Eligible patients, aged 6ā17Ā years, were diagnosed with ADHD and about to begin treatment with Equasym XLĀ®. Effectiveness was assessed by physicians using the clinical global impression (CGI) severity and improvement scales; teachers and parents completed questionnaires evaluating ADHD symptoms and behavioural problems (DAYAS, FBB-ADHD and SDQ-P). Assessments were carried out at baseline, after 1ā3 and 6ā12Ā weeks of treatment. Of 852 enrolled patients, 822 were evaluable; 25.30% were treatment naĆÆve, 69.84% had previously received different MPH formulations, and 4.87% had received other medications. ADHD symptoms improved from baseline to last visit for the majority of patients for all outcome measures. According to physician ratings of core ADHD symptoms, 75.73% of patients showed improvements on the CGI-Improvement scale, 17.77% had no change, and 6.50% worsened. In teacher and parent ratings, the effectiveness of Equasym XLĀ® was rated better than prior therapy at all measured time points across the day, particularly late morning (teachers) and early afternoon (parents). Equasym XLĀ® was generally well tolerated; only 3.16% of patients permanently discontinued treatment due to adverse events. Equasym XLĀ® is effective and well tolerated in daily clinical practice
Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils
It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model
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