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Most monogenic disorders are caused by a pathologic deficit or excess of a single transcript and/or protein. Given that small molecules, including drugs, can affect levels of mRNA and protein, the pharmacologic normalization of such pathogenic dosage represents a possible therapeutic approach for such conditions. Here, we review the literature exploring pharmacologic modulation of mRNA and/or protein levels for disorders with paralogous modifier genes, for haploinsufficient disorders (insufficient gene-product), as well as toxic gain-of-function disorders (surplus or pathologic gene-product). We also discuss challenges facing the development of rare disease therapy by pharmacologic modulation of mRNA and protein. Finally, we lay out guiding principles for selection of disorders which may be amenable to this approach.

Host-parasite checklists are essential resources in ecological parasitology, and are regularly used as sources of data in comparative studies of parasite species richness across host species, or of host specificity among parasite species. However, checklists are only useful datasets if they are relatively complete, that is, close to capturing all host–parasite associations occurring in a particular region. Here, we use three approaches to assess the completeness of 25 checklists of metazoan parasites in vertebrate hosts from various geographic regions. First, treating checklists as interaction networks between a set of parasite species and a set of host species, we identify networks with a greater connectance (proportion of realized host–parasite associations) than expected for their size. Second, assuming that the cumulative rise over time in the number of known host–parasite associations in a region tends toward an asymptote as their discovery progresses, we attempt to extrapolate the estimated total number of existing associations. Third, we test for a positive correlation between the number of published reports mentioning an association and the time since its first record, which is expected because observing and reporting host–parasite associations are frequency-dependent processes. Overall, no checklist fared well in all three tests, and only three of 25 passed two of the tests. These results suggest that most checklists, despite being useful syntheses of regional host–parasite associations, cannot be used as reliable sources of data for comparative analyses. [ABSTRACT FROM AUTHOR]

Abstract: Among the various direct numerical simulation (DNS) methods dedicated to multiphase flow, the front-tracking methods that use a Lagrangian mesh to describe explicitly the interfaces are generally considered as a very accurate and complex method. In this family of methods, while a fine Lagrangian mesh is desirable for a better representation of the interfacial area, the surface forces and the bubble or droplet volume, one cannot arbitrarily choose the Lagrangian mesh size. Indeed, the Lagrangian mesh displacement algorithm is unstable if the number of Lagrangian degrees of freedom does not match the number of involved Eulerian velocity points. As a consequence, in traditional front-tracking implementations, an accurate description of the interfaces is expensive in terms of Eulerian mesh cells. We demonstrate that a front-tracking interface smoothing (FTIS) method can reduce the constraints on the mesh sizes. It consists in damping the highest spatial frequency components of the Lagrangian mesh to compensate for the lack of Eulerian velocity points. The test case of fundamental proper frequency of a bubble proves the validity of the FTIS method. An example of a 3D-bubble rising shows the interest and the potential applications of the FTIS method. [Copyright &y& Elsevier]

Introduction:CAEP recently developed the acute atrial fibrillation (AF) and flutter (AFL) [AAFF] Best Practices Checklist to promote optimal care and guidance on cardioversion and rapid discharge of patients with AAFF. We sought to assess the impact of implementing the Checklist into large Canadian EDs. Methods:We conducted a pragmatic stepped-wedge cluster randomized trial in 11 large Canadian ED sites in five provinces, over 14 months. All hospitals started in the control period (usual care), and then crossed over to the intervention period in random sequence, one hospital per month. We enrolled consecutive, stable patients presenting with AAFF, where symptoms required ED management. Our intervention was informed by qualitative stakeholder interviews to identify perceived barriers and enablers for rapid discharge of AAFF patients. The many interventions included local champions, presentation of the Checklist to physicians in group sessions, an online training module, a smartphone app, and targeted audit and feedback. The primary outcome was length of stay in ED in minutes from time of arrival to time of disposition, and this was analyzed at the individual patient-level using linear mixed effects regression accounting for the stepped-wedge design. We estimated a sample size of 800 patients. Results:We enrolled 844 patients with none lost to follow-up. Those in the control (N = 316) and intervention periods (N = 528) were similar for all characteristics including mean age (61.2 vs 64.2 yrs), duration of AAFF (8.1 vs 7.7 hrs), AF (88.6% vs 82.9%), AFL (11.4% vs 17.1%), and mean initial heart rate (119.6 vs 119.9 bpm). Median lengths of stay for the control and intervention periods respectively were 413.0 vs. 354.0 minutes (P < 0.001). Comparing control to intervention, there was an increase in: use of antiarrhythmic drugs (37.4% vs 47.4%; P < 0.01), electrical cardioversion (45.1% vs 56.8%; P < 0.01), and discharge in sinus rhythm (75.3% vs. 86.7%; P < 0.001). There was a decrease in ED consultations to cardiology and medicine (49.7% vs 41.1%; P < 0.01), but a small but insignificant increase in anticoagulant prescriptions (39.6% vs 46.5%; P = 0.21). Conclusion:This multicenter implementation of the CAEP Best Practices Checklist led to a significant decrease in ED length of stay along with more ED cardioversions, fewer ED consultations, and more discharges in sinus rhythm. Widespread and rigorous adoption of the CAEP Checklist should lead to improved care of AAFF patients in all Canadian EDs.

A multi-SISO or a MIMO design approach is proposed for the robust control of uncertain LTI square MIMO plants, depending on the extent of the plant’s diagonal nature. For the multi-SISO approach, new multivariable frequency uncertainty domains are defined using the Gershgorin and the small gains theorems. These domains are based both on the structured frequency uncertainty domains related to the diagonal elements of the plant transfer matrix, and on the Gershgorin circles related to the corresponding column elements. Each element of the diagonal controller can be thus designed independently of the others using the SISO Crone design method. The totally MIMO approach is based on the optimization of an open-loop diagonal transfer matrix to minimize the stability margin variations of the perturbed diagonal elements of the closed-loop transfer matrix.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous autosomal dominant disease, caused by mutations in several sarcomeric protein genes. So far, seven genes have been shown to be associated with the disease with the β-myosin heavy chain (MYH7) and the cardiac myosin binding protein C (MYBPC3) genes being the most frequently involved. We performed electrocardiography (ECG) and echocardiography in 15 subjects with hypertrophic cardiomyopathy from a French Caribbean family. Genetic analyses were performed on genomic DNA by haplotype analysis with microsatellite markers at each locus involved and mutation screening by single strand conformation polymorphism analysis. Based on ECG and echocardiography, eight subjects were affected and presented a classical phenotype of hypertrophic cardiomyopathy. Two new mutations cosegregating with the disease were found, one located in the MYH7 gene exon 15 (Glu483Lys) and the other in the MYBPC3 gene exon 30 (Glu1096 termination codon). Four affected subjects carried the MYH7 gene mutation, two the MYBPC3 gene mutation, and two were doubly heterozygous for the two mutations. The doubly heterozygous patients exhibited marked left ventricular hypertrophy, which was significantly greater than in the other affected subjects.We report for the first time the simultaneous presence of two pathological mutations in two different genes in the context of familial hypertrophic cardiomyopathy. This double heterozygosity is not lethal but is associated with a more severe phenotype.

Sounds and musical notes are a part of most personal computers. The Apple II+ has a wide range of sounds and notes. The provided programs exercise these features of the Apple and introduce the programmer to several related techniques.

Apple Music Writer allows the user to create music and reproduce favorite songs. Instructions are given on how to use the program commands. Hints are offered on easier use of the program. A program listing is included.

This paper deals with the application of the CRONE control to the ‘flexible transmission’ benchmark problem. The CRONE control strategy based on complex non-integer integration is presented. Significant modifications are provided to control the resonance modes of the plant. The benchmark problem and the synthesis of the controller are described. Simulation and experimental results are given.

ABSTRACTCationic lipid-mediated gene transfer of cystic fibrosis transmembrane conductance regulator (CFTR) cDNA represents a promising approach for treatment of cystic fibrosis (CF). Here, we report on the structures of several novel cationic lipids that are effective for gene delivery to the lungs of mice. An amphiphile (#67) consisting of a cholesterol anchor linked to a spermine headgroup in a T-shape configuration was shown to be particularly efficacious. An optimized formulation of #67 and plasmid vector encoding chloramphenicol acetyl-transferase (CAT) was capable of generating up to 1 g of CAT enzyme/lung following intranasal instillation into BALB/c mice. This represents a 1,000-fold increase in expression above that obtained in animals instilled with naked pDNA alone and is greater than 100-fold more active than cationic lipids used previously for CFTRgene expression. When directly compared with adenovirus-based vectors containing similar transcription units, the number of molecules of gene product expressed using lipid-mediated transfer was equivalent to vector administration at multiplicities of infection ranging from 1 to 20. The level of transgene expression in the lungs of BALB/c mice peaked between days 1 and 4 post-instillation, followed by a rapid decline to approximately 20% of the maximal value by day 7. Undiminished levels of transgene expression in the lung could be obtained following repeated intranasal administration of #67:DOPE:pCF1-CAT in nude mice. Transfection of cells with formulations of #67:DOPE:pCF1-CFTR generated cAMP-stimulated CFTR chloride channel and fluid transport activities, two well-characterized defects associated with CF cells. Taken together, the data demonstrate that cationic lipid-mediated gene delivery and expression of CFTRin CF lungs is a viable and promising approach for treatment of the disease.

Measurements of NO2, HCHO, and H2O2 were made by the highly specific method of mid infra-red absorption spectroscopy using tunable diode lasers (TDLAS) during the 1988 Polarstern expedition. The TDLAS data are compared to those obtained during the cruise using less direct methods. Southern Hemisphere NO2 levels suggest nett photochemical destruction of O3 in the boundary layer. Northern Hemisphere HCHO averaged 0.47±0.2 ppbv; the HCHO measurements are used in a simple calculation to estimate OH noontime maxima of 3–6×106 cm-3.

The article presents the study on an assymetric laser communication (lasercom) developed by the U.S. Naval Research Laboratory for small unmanned aerial systems (UASs). It states that the lasercom was developed due to the increasing reliance on UASs and the development of sensors that require higher-bandwidths. It also describes the components of the airborne lasercom transceiver and the Dakota Wingpod Lasercom System.

Blended negative electrodes with a mix of graphite and silicon are attractive solutions to extend the energy density of lithium-ion batteries. Given the huge volume expansion of silicon, the relative lithiation/delithiation of both active materials upon cycling is crucial to determine the mechanical behavior of the electrode. It is complicated however by the potential hysteresis displayed by silicon. We focus on a blended anode with 16 wt% of silicon carbon composite (SiC-C) at a gravimetric capacity of 1500 mAh.g?1mixed with 84 wt% graphite. A multi-scale porous electrode model with three different hierarchical units has been developed to account for the morphology of the SiC-C composed of nanoflakes of silicon embedded in a carbon matrix. The developed physics-based model is parametrized with appropriate experiments and validated for two electrodes loadings and various operating conditions. The validated model allows to probe the lithiation competition between the silicon and the carbon within the composite and the graphite. It is able to capture the streaking features revealed by synchrotron experiments. In particular, we show that at higher C-rates, the lithiation of the silicon is delayed and reduced compared to the graphite one. Quantifying this relative competition is valuable as aging effects are significantly accelerated by the expansion of the silicon.

La traçabilité des Dispositifs médicaux implantables (DMI) est un enjeu majeur des établissements de santé. Au CHU de Montpellier le processus repose sur une traçabilité papier initiale au bloc opératoire puis une saisie informatique par l’Equipe pharmaceutique (EP), source d’erreurs potentielles. Pour sécuriser le processus, un contrôle de cohérence entre actes et DMI en sus des GHS a été implémenté.

Introduction:In the province of Québec, roughly 20% of the population lives in rural areas. Rural emergency departments (EDs) face different challenges than their urban counterparts. Yet, few studies have sought to understand these challenges. This study aims to survey Québec’s emergency physicians to: 1) identify problems specific to rural EDs, 2) find solutions for improving accessibility and quality of care offered in rural regions and, 3) rank solutions in order of priority. These results will allow data triangulation with other of our studies that seek to identify challenges faced by rural EDs and potential solutions. Methods:During the 2016 annual conference of the Québec Emergency Physicians’ Association, we asked physicians and residents (including those from urban EDs), to complete a survey about the challenges faced by rural EDs. The survey contained two sections. The first took the form of open-ended questions in which respondents could write three challenges about accessibility and quality of care in rural EDs (objective 1) and three solutions to address these challenges (objective 2). The second section listed 11 potential solutions identified in our previous study. The solutions were ranked based on their priority level on a five-point Likert scale that ranged from “not a priority” to “an absolute priority” (objective 3). We added the total number of points for each solution and produced a ranking list. Results:Ninety-one physicians out of the 417 at the conference completed the survey; 58% came from urban EDs and 42% from rural EDs. Open-ended questions suggest that access to specialists and interfacility transfers are the principal challenges faced by rural EDs. The top five solutions identified as the highest priorities were: 1) care protocols, 2) improvement of interfacility transfers, 3) training with simulators, 4) targeted ultrasound and, 5) implementation of staff retention and recruitment strategies. Conclusion:This study is relevant and useful as roughly a quarter of attendants at the conference spontaneously volunteered to help identify and prioritize solutions to foster the accessibility and quality of care in rural EDs. Furthermore, it represents a stepping stone for our recently-launched wide-scope study, Urgences Rurales 360, that aims to explore problems faced by every of the 28 rural EDs in Québec and the solutions that could be implemented to resolve them.

Bluetongue virus (BTV) is an economically important arbovirus of ruminants transmitted by Culicoides biting midges. Vector control using residual spraying or application to livestock is recommended by many authorities to reduce BTV transmission; however, the impact of these measures in terms of both inflicting mortality on Culicoides and subsequently upon BTV transmission is unclear. This study consisted of a standardized World Health Organization laboratory assay to determine the susceptibility of European Culicoides species to deltamethrin and a field trial based upon allowing individuals of a laboratory strain of Culicoides nubeculosus Meigen to feed upon sheep treated with Butox 7.5 pour-on (a deltamethrin-based topical formulation). Susceptibility in the laboratory trial was higher in colony C. nubeculosus (24-h LC90 = 0.00106%), than in field populations of Culicoides obsoletus Meigen (24-h LC90 = 0.00203%) or Culicoides imicola Kieffer (24-h LC90 = 0.00773%). In the field, the pour-on formulation was tested with a total of 816 C. nubeculosus specimens fed upon on the thigh of treated sheep. The study revealed a maximum mortality rate of 49% at 4 d postapplication, and duration of lethal effect was predicted to be as short as 10 d, despite testing being carried out with a highly susceptible strain. The reasons for this low efficacy are discussed with reference both to the potential for lack of spread of the active ingredient on the host and feeding patterns of the major potential vector species on the sheep host. Practical implications for vector control strategies during BTV incursions are also detailed.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.