Characteristics of a population-based multiple sclerosis cohort treated with disease-modifying drugs in a universal healthcare setting

BACKGROUND: Relatively little is known about the use of disease-modifying drugs (DMDs) for multiple sclerosis (MS) in the population-based universal healthcare setting. This study aimed to describe the characteristics of a population-based cohort with MS and their DMD exposure in four Canadian provinces. METHODS: We identified all adults (aged ≥18 years) with MS using linked population-based health administrative data. Individuals were followed from the most recent of their first MS or demyelinating event or 1 January 1996(study entry), to the earliest of death, emigration, or 31 March 2018(study end). Cohort characteristics examined included sex, age, socioeconomic status, and comorbidity burden. RESULTS: Overall, 10,418/35,894 (29%) of MS cases filled a DMD prescription during the 22-year study period. Most were women (n = 7,683/10,418;74%), and 17% (n = 1,745/10,418) had some comorbidity (Charlson Comorbidity Index≥1) at study entry. Nearly 20% (n = 1,745/10,418) were aged ≥50 when filling their first DMD; the mean age was 39.6 years. CONCLUSIONS: Almost 1 in 6 people with MS had at least some comorbidity, and nearly 1 in 6 were ≥50 years old at the time of their first DMD. As these individuals are typically excluded from clinical trials, findings illustrate the need to understand the harms and benefits of DMD use in these understudied groups

The effect of body shape and swimsuit type on the comfort of Chinese women wearing swimsuits

Among the fitness and body shaping exercises of Chinese women, swimming has become an increasingly popular sporting activity. Swimsuits are fundamental to participation in this sport and paramount to achieving the wearers’ aim of participation. A survey of 3348 Chinese women showed that body fit is central to the purchase of a swimsuit, whether one piece or two piece, with the two-piece swimsuit proving the most popular in terms of comfort. This survey revealed that the comfort of a swimsuit is relative to the design variables of the swimsuit style, the material/body cover factor and, informed by the female form, body size and body shape. This is particularly pertinent in both the right and left anterior mammary regions and also the left lateral mammary region for the female wearer to stay comfortable during swimming when she moves in the water. This study investigated the factors that affect the comfort of women wearing swimsuits when they swim. The two-piece swimsuit was considered the most comfortable. It was also found that swimsuits negatively affect women’s chest area. These results present important considerations for swimsuit manufacturers

Generation of tooth profile for roots rotor based on virtual linkage associated with Assur group

This article, for the first time, presents the generation of Roots rotor tooth profiles based on an Assur-group-associated virtual linkage method. Taking the original Roots rotor as an example, structure and geometry of the Roots rotor are introduced, and based on the principle of inversion, an equivalent virtual linkage is identified for generating dedendum tooth profile of the rotor. Using linkage decomposition associated with elemental Assur groups, algorithm for computing the tooth curve is constructed leading to the explicit expression of rotor profile and the corresponding numerical simulation, verifying the validity of the proposed approach. For demonstration purpose, the virtual linkage method is then extended to the generation of tooth profiles for the variants of Roots rotors with arc-cycloidal curves and arc-involute curves. Integrated with computer-aided design, computer-aided engineering and computer-aided manufacturing software platforms, as well as the three-dimensional printing technology, this article provides an efficient and intuitive approach for Roots rotor system design, analysis and development

To dash or to dawdle: verb-associated speed of motion influences eye movements during spoken sentence comprehension

In describing motion events verbs of manner provide information about the speed of agents or objects in those events. We used eye tracking to investigate how inferences about this verb-associated speed of motion would influence the time course of attention to a visual scene that matched an event described in language. Eye movements were recorded as participants heard spoken sentences with verbs that implied a fast (“dash”) or slow (“dawdle”) movement of an agent towards a goal. These sentences were heard whilst participants concurrently looked at scenes depicting the agent and a path which led to the goal object. Our results indicate a mapping of events onto the visual scene consistent with participants mentally simulating the movement of the agent along the path towards the goal: when the verb implies a slow manner of motion, participants look more often and longer along the path to the goal; when the verb implies a fast manner of motion, participants tend to look earlier at the goal and less on the path. These results reveal that event comprehension in the presence of a visual world involves establishing and dynamically updating the locations of entities in response to linguistic descriptions of events

Cyclic Nucleotide-Gated Channels Contribute to Thromboxane A2-Induced Contraction of Rat Small Mesenteric Arteries

Background: Thromboxane A 2 (TxA 2)-induced smooth muscle contraction has been implicated in cardiovascular, renal and respiratory diseases. This contraction can be partly attributed to TxA2-induced Ca 2+ influx, which resulted in vascular contraction via Ca 2+-calmodulin-MLCK pathway. This study aims to identify the channels that mediate TxA2-induced Ca 2+ influx in vascular smooth muscle cells. Methodology/Principal Findings: Application of U-46619, a thromboxane A2 mimic, resulted in a constriction in endothelium-denuded small mesenteric artery segments. The constriction relies on the presence of extracellular Ca 2+, because removal of extracellular Ca 2+ abolished the constriction. This constriction was partially inhibited by an L-type Ca 2+ channel inhibitor nifedipine (0.5–1 mM). The remaining component was inhibited by L-cis-diltiazem, a selective inhibitor for CNG channels, in a dose-dependent manner. Another CNG channel blocker LY83583 [6-(phenylamino)-5,8-quinolinedione] had similar effect. In the primary cultured smooth muscle cells derived from rat aorta, application of U46619 (100 nM) induced a rise in cytosolic Ca 2+ ([Ca 2+]i), which was inhibited by L-cis-diltiazem. Immunoblot experiments confirmed the presence of CNGA2 protein in vascular smooth muscle cells. Conclusions/Significance: These data suggest a functional role of CNG channels in U-46619-induced Ca 2+ influx and contraction of smooth muscle cells

Near-field examination of perovskite-based superlenses and superlens-enhanced probe-object coupling

A planar slab of negative index material works as a superlens with sub-diffraction-limited imaging resolution, since propagating waves are focused and, moreover, evanescent waves are reconstructed in the image plane. Here, we demonstrate a superlens for electric evanescent fields with low losses using perovskites in the mid-infrared regime. The combination of near-field microscopy with a tunable free-electron laser allows us to address precisely the polariton modes, which are critical for super-resolution imaging. We spectrally study the lateral and vertical distributions of evanescent waves around the image plane of such a lens, and achieve imaging resolution of wavelength/14 at the superlensing wavelength. Interestingly, at certain distances between the probe and sample surface, we observe a maximum of these evanescent fields. Comparisons with numerical simulations indicate that this maximum originates from an enhanced coupling between probe and object, which might be applicable for multifunctional circuits, infrared spectroscopy, and thermal sensors.Comment: 20 pages, 6 figures, published as open access article in Nature Communications (see http://www.nature.com/ncomms/

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Lung glutathione adaptive responses to cigarette smoke exposure

<p>Abstract</p> <p>Background</p> <p>Smoking tobacco is a leading cause of chronic obstructive pulmonary disease (COPD), but although the majority of COPD cases can be directly related to smoking, only a quarter of smokers actually develop the disease. A potential reason for the disparity between smoking and COPD may involve an individual's ability to mount a protective adaptive response to cigarette smoke (CS). Glutathione (GSH) is highly concentrated in the lung epithelial lining fluid (ELF) and protects against many inhaled oxidants. The changes in GSH that occur with CS are not well investigated; therefore the GSH adaptive response that occurs with a commonly utilized CS exposure was examined in mice.</p> <p>Methods</p> <p>Mice were exposed to CS for 5 h after which they were rested in filtered air for up to 16 h. GSH levels were measured in the ELF, bronchoalveolar lavage cells, plasma, and tissues. GSH synthesis was assessed by measuring γ-glutamylcysteine ligase (GCL) activity in lung and liver tissue.</p> <p>Results</p> <p>GSH levels in the ELF, plasma, and liver were decreased by as much as 50% during the 5 h CS exposure period whereas the lung GSH levels were unchanged. Next, the time course of rebound in GSH levels after the CS exposure was examined. CS exposure initially decreased ELF GSH levels by 50% but within 2 h GSH levels rebound to about 3 times basal levels and peaked at 16 h with a 6-fold increase and over repeat exposures were maintained at a 3-fold elevation for up to 2 months. Similar changes were observed in tissue GCL activity which is the rate limiting step in GSH synthesis. Furthermore, elevation in ELF GSH levels was not arbitrary since the CS induced GSH adaptive response after a 3d exposure period prevented GSH levels from dropping below basal levels.</p> <p>Conclusions</p> <p>CS exposures evoke a powerful GSH adaptive response in the lung and systemically. These data suggests there may be a sensor that sets the ELF GSH adaptive response to prevent GSH levels from dipping below basal levels. Factors that disrupt GSH adaptive responses may contribute to the pathophysiology of COPD.</p

Evidence based post graduate training. A systematic review of reviews based on the WFME quality framework

<p>Abstract</p> <p>Background</p> <p>A framework for high quality in post graduate training has been defined by the World Federation of Medical Education (WFME). The objective of this paper is to perform a systematic review of reviews to find current evidence regarding aspects of quality of post graduate training and to organise the results following the 9 areas of the WFME framework.</p> <p>Methods</p> <p>The systematic literature review was conducted in 2009 in Medline Ovid, EMBASE, ERIC and RDRB databases from 1995 onward. The reviews were selected by two independent researchers and a quality appraisal was based on the SIGN tool.</p> <p>Results</p> <p>31 reviews met inclusion criteria. The majority of the reviews provided information about the training process (WFME area 2), the assessment of trainees (WFME area 3) and the trainees (WFME area 4). One review covered the area 8 'governance and administration'. No review was found in relation to the mission and outcomes, the evaluation of the training process and the continuous renewal (respectively areas 1, 7 and 9 of the WFME framework).</p> <p>Conclusions</p> <p>The majority of the reviews provided information about the training process, the assessment of trainees and the trainees. Indicators used for quality assessment purposes of post graduate training should be based on this evidence but further research is needed for some areas in particular to assess the quality of the training process.</p