Effects of experience and opponents on pacing behavior and 2-km cycling performance of novice youths

Purpose: To study the pacing behavior and performance of novice youth exercisers in a controlled laboratory setting. Method: Ten healthy participants (seven male, three female, 15.8 ± 1.0 years) completed four, 2-km trials on a Velotron cycling ergometer. Visit 1 was a familiarization trial. Visits 2 to 4 involved the following conditions, in randomized order: no opponent (NO), a virtual opponent (starting slow and finishing fast) (OP-SLOWFAST), and a virtual opponent (starting fast and finishing slow) (OP-FASTSLOW). Repeated measurement ANOVAs (p < .05) were used to examine differences in both pacing behavior and also performance related to power output, finishing- and split times, and RPE between the four successive visits and the three conditions. Expected performance outcome was measured using a questionnaire. Results: Power output increased (F3,27 = 5.651, p = .004, η2p = .386) and finishing time decreased (F3,27 = 9.972, p .05). Conclusion: Performance was improved by an increase in experience after one visit, parallel with the ability to anticipate future workload

Drafting in long-track speed skating team pursuit on the ice rink

Drafting is distinctive for team pursuit races in long-track speed skating. This study aims to compare the impact of drafting on physical intensity (heart rate [HR]) and perceived intensity (ratings of perceived exertion [RPE]) per drafting position. Eighteen skilled male (n = 9) and female (n = 9) skaters (20.0 ± 4.8 years) skated three trials, in first, second or third position, with consistent average velocity (F2,10 = 2.30, p = 0.15, ηp2 = 0.32). Differences in HR and RPE (Borg CR−10 scale) were compared within-subjects (three positions) using a repeated-measures ANOVA (p &lt; 0.05). Compared to the first position, HR was lower in the second (benefit 3.2%) and third (benefit 4.7%) position and lower in third compared to second position (benefit 1.5%), observed in 10 skaters (F2,28 = 28.9, p &lt; 0.001, ηp2= 0.67). RPE was lower when comparing second (benefit 18.5%) and third (benefit 16.8%) position to first (F1.3,22.1 = 7.02, p &lt; 0.05, ηp2= 0.29) and similar for third and second positions., observed in 8 skaters. Even though the physical intensity was lower when drafting in third versus second position, the perceived intensity was equal. There were large interindividual differences between skaters. Coaches are advised to adopt a multidimensional, tailored approach when selecting and training skaters for a team pursuit.</p

Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (Tyr(B26)) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr(B26)]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (Tyr(B16), Phe(B24), Phe(B25), 3-I-Tyr(B26), and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-Tyr(B26)]insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr(B26) in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-Tyr(B26) engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins

The Reorientation of T-Cell Polarity and Inhibition of Immunological Synapse Formation by CD46 Involves Its Recruitment to Lipid Rafts

Many infectious agents utilize CD46 for infection of human cells, and therapeutic applications of CD46-binding viruses are now being explored. Besides mediating internalization to enable infection, binding to CD46 can directly alter immune function. In particular, ligation of CD46 by antibodies or by measles virus can prevent activation of T cells by altering T-cell polarity and consequently preventing the formation of an immunological synapse. Here, we define a mechanism by which CD46 reorients T-cell polarity to prevent T-cell receptor signaling in response to antigen presentation. We show that CD46 associates with lipid rafts upon ligation, and that this reduces recruitment of both lipid rafts and the microtubule organizing centre to the site of receptor cross-linking. These data combined indicate that polarization of T cells towards the site of CD46 ligation prevents formation of an immunological synapse, and this is associated with the ability of CD46 to recruit lipid rafts away from the site of TCR ligation

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial

markdownabstract__Background:__ The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. __Methods:__ This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. __Discussion:__ OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. Trial registration:NTR4499. Registered on 7 April 2014

Internally Controlled, Generic Real-Time PCR for Quantification and Multiplex Real-Time PCR with Serotype-Specific Probes for Serotyping of Dengue Virus Infections

Dengue has become a global public health problem and a sensitive diagnostic test for early phase detection can be life saving. An internally controlled, generic real-time PCR was developed and validated by testing serial dilutions of a DENV positive control RNA in the presence of a fixed amount of IC with results showing a good linearity (R2 = 0.9967) and a LOD of at least 1.95 × 104 copies/mL. Application of the generic PCR on 136 patient samples revealed a sensitivity of 95.8% and specificity of 100%. A newly developed multiplex real-time PCR with serotype-specific probes allowed the serotyping of DENV for 80 out of 92 (87%) generic real-time PCR positive patients. Combined these real-time PCRs offer a convenient diagnostic tool for the sensitive and specific quantification of DENV in clinical specimens with the possibility for serotyping

Burglary in London: insights from statistical heterogeneous spatial point processes

To obtain operational insights regarding the crime of burglary in London, we consider the estimation of the effects of covariates on the intensity of spatial point patterns. Inspired by localized properties of criminal behaviour, we propose a spatial extension to mixtures of generalized linear models from the mixture modelling literature. The Bayesian model proposed is a finite mixture of Poisson generalized linear models such that each location is probabilistically assigned to one of the groups. Each group is characterized by the regression coefficients, which we subsequently use to interpret the localized effects of the covariates. By using a blocks structure of the study region, our approach enables specifying spatial dependence between nearby locations. We estimate the proposed model by using Markov chain Monte Carlo methods and we provide a Python implementation

Assessing the experience of person‐centred coordinated care of people with chronic conditions in the Netherlands: Validation of the Dutch P3CEQ

Background: 'patient experience’ is becoming increasingly important. For this purpose, the Person‐Centred Coordinated Care Experience Questionnaire (P3CEQ) was developed in the United Kingdom, and translated into several languages. Aim: This study aimed to assess the internal and construct validity of the Dutch P3CEQ to capture the experience of person‐centred coordinated care of people with chronic conditions in the Netherlands. Participants and Methods: Adults with chronic conditions (N = 1098) completed the Dutch P3CEQ, measures of health literacy and patient activation, and reported the use and perceived quality of care services. Data analysis included Principal Component and reliability analysis (internal validity), analysis of variance and Student's T‐tests (construct validity). Results: The two‐component structure found was pretty much the same as in the UK validation study. Sociodemographic correlates also resembled those found in the United Kingdom. Women, persons who were less educated, less health‐literate or less activated experienced less person‐centred coordinated care. P3CEQ scores correlated positively with general practitioner performance scores and quality ratings of the total care received. Conclusion: The Dutch P3CEQ is a valid instrument to assess the experience of person‐centred coordinated care among people with chronic conditions in the Netherlands. Awareness of inequity and more attention to communication skills in professional training are needed to ensure that care professionals better recognize the needs of women, lower educated or less health‐literate persons, and improve their experiences of care. Patient Contribution: The P3CEQ has been developed in collaboration with a range of stakeholders. Eighteen persons with (multiple) chronic conditions participated as patient representatives and codesign experts in (four) codesign workshops. Other patient representatives participated in cognitive testing of the English‐language instrument. The usability of the P3CEQ to capture the experience of person‐centred coordinated care of older persons has been examined by interviewing 228 older European service users, including 13 living in the Netherlands, as part of the SUSTAIN project. More than a thousand persons with chronic conditions participated in the validation study of the Dutch P3CEQ