Commentary on strategies for switching antipsychotics

Both the new generation of antipsychotics and the more traditional antipsychotic drugs produce an important and meaningful improvement in patients with schizophrenia, but most patients are neither cured nor free of symptoms. As a consequence, it is common to switch from one drug to another in the hope of obtaining a better response. All antipsychotic drugs produce some side effects, so switching can also be a tolerance issue. There are reports in the literature on the tactics of switching: abrupt discontinuation, cross tapering, starting a patient on a new drug while continuing with the old drug until the new drug has reached a steady state, or some variation on these tactics. In this issue, Ganguli et al. have carried out a randomized switching study, the data from which indicates the tactics that might be optimal. We put this paper into context, provide a critique and describe indications for switching

D2 receptor occupancy of olanzapine pamoate depot using positron emission tomography : an open-label study in patients with schizophrenia

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D2 receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D2 occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D2 receptor occupancy, as measured by [11C]-raclopride PET, was 69% on oral olanzapine (5–20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D2 receptor occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, Pless than or equal to0.001). OP depot resulted in mean D2 receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.peer-reviewe

A systematic review of methods for increasing vegetable consumption in early childhood

PURPOSE OF REVIEW: This study aims to synthesise the body of research investigating methods for increasing vegetable consumption in 2- to 5-year-old children, while offering advice for practitioners. RECENT FINDINGS: Repeated exposure is a well-supported method for increasing vegetable consumption in early childhood and may be enhanced with the inclusion of non-food rewards to incentivise tasting. Peer models appear particularly effective for increasing 2-5-year-olds' vegetable consumption. There is little evidence for the effectiveness of food adaptations (e.g. flavour-nutrient learning) for increasing general vegetable intake among this age group, although they show some promise with bitter vegetables. SUMMARY: This review suggests that practitioners may want to focus their advice to parents around strategies such as repeated exposure, as well as the potential benefits of modelling and incentivising tasting with non-food rewards. Intervention duration varies greatly, and considerations need to be made for how this impacts on success

A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation

[EN] Curve squeal is an intense tonal noise occurring when a rail vehicle negotiates a sharp curve. The phenomenon can be considered to be chaotic, with a widely differing likelihood of occurrence on different days or even times of day. The term curve squeal may include several different phenomena with a wide range of dominant frequencies and potentially different excitation mechanisms. This review addresses the different squeal phenomena and the approaches used to model squeal noise; both time-domain and frequency-domain approaches are discussed and compared. Supporting measurements using test rigs and field tests are also summarised. A particular aspect that is addressed is the excitation mechanism. Two mechanisms have mainly been considered in previous publications. In many early papers the squeal was supposed to be generated by the so-called falling friction characteristic in which the friction coefficient reduces with increasing sliding velocity. More recently the mode coupling mechanism has been raised as an alternative. These two mechanisms are explained and compared and the evidence for each is discussed. Finally, a short review is given of mitigation measures and some suggestions are offered for why these are not always successful.Squicciarini, G.; Thompson, D.; Ding, B.; Baeza González, LM. (2018). A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation. Notes on Numerical Fluid Mechanics and Multidisciplinary Design. 139:3-41. https://doi.org/10.1007/978-3-319-73411-8_1S341139Anderson, D., Wheatley, N., Fogarty, B., Jiang, J., Howie, A., Potter, W.: Mitigation of curve squeal noise in Queensland, New South Wales and South Australia. In: Conference on Railway Engineering. pp. 625–636, Perth, Australia (2008)Hanson, D., Jiang, J., Dowdell, B., Dwight, R.: Curve squeal: causes, treatments and results. 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Veh. Syst. Dyn. 44(sup1), 261–271 (2006)Giménez, J.G., Alonso, A., Gómez, E.: Introduction of a friction coefficient dependent on the slip in the FastSim algorithm. Veh. Syst. Dyn. 43(4), 233–244 (2005)Chiello, O., Ayasse, J.B., Vincent, N., Koch, J.R.: Curve squeal of urban rolling stock—part 3: theoretical model. J. Sound Vib. 293(3), 710–727 (2006)Collette, C.: Importance of the wheel vertical dynamics in the squeal noise mechanism on a scaled test bench. Shock Vibr. 19(2), 145–153 (2012)Brunel, J.F., Dufrénoy, P., Naït, M., Muñoz, J.L., Demilly, F.: Transient models for curve squeal noise. J. Sound Vib. 293(3), 758–765 (2006)Glocker, C., Cataldi-Spinola, E., Leine, R.I.: Curve squealing of trains: measurement, modelling and simulation. J. Sound Vib. 324(1), 365–386 (2009)Pieringer, A.: A numerical investigation of curve squeal in the case of constant wheel/rail friction. J. Sound Vib. 333(18), 4295–4313 (2014)Pieringer, A., Kropp, W.: A time-domain model for coupled vertical and tangential wheel/rail interaction—a contribution to the modelling of curve squeal. In: Maeda, T., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 118, pp. 221–229. Springer, Heidelberg (2012)Pieringer, A., Baeza, L., Kropp. W.: Modelling of railway curve squeal including effects of wheel rotation. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 417–424. Springer, Heidelberg (2015)Zenzerovic, I., Pieringer, A., Kropp. W.: Towards an engineering model for curve squeal. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 433–440. Springer, Heidelberg (2015)Zenzerovic, I., Kropp, W., Pieringer, A.: An engineering time-domain model for curve squeal: tangential point-contact model and Green’s functions approach. J. Sound Vib. 376, 149–165 (2016)Pieringer, A., Torstensson, P.T., Giner, J., Baeza, L.: Investigation of railway curve squeal using a combination of frequency- and time-domain models. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp 81–93. Springer, Heidelberg (2018)Chen, G.X., Xiao, J.B., Liu, Q.Y., Zhou. Z.R.: Complex eigenvalue analysis of railway curve squeal. In: Schulte-Werning, B., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 99, pp. 433–439. Springer, Heidelberg (2008)Fourie, D.J., Gräbe, P.J., Heyns, P.S., Fröhling, R.D.: Analysis of wheel squeal due to unsteady longitudinal creepage using the complex eigenvalue method. In: Anderson, D., et al. (eds.) 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Wear 265(9), 1309–1316 (2008)Fletcher, D.I., Lewis, S.: Creep curve measurement to support wear and adhesion modelling, using a continuously variable creep twin disc machine. Wear 298–299, 57–65 (2013)Fletcher, D.I.: A new two-dimensional model of rolling–sliding contact creep curves for a range of lubrication types. Proc. Inst. Mech. Eng. Part J: J. Eng. Tribol. 227(6), 529–537 (2013)Matsumoto, A., Sato, Y., Ono, H., Wang, Y., Yamamoto, M., Tanimoto, M., Oka, Y.: Creep force characteristics between rail and wheel on scaled model. Wear 253(1), 199–203 (2002)Janssens, M.H.A., van Vliet, W.J., Kooijman, P.P., De Beer, F.G.: Curve squeal of railbound vehicles (part 3): measurement method and results. In: Proceedings of Internoise, vol. 3, pp. 1568–1571, Nice, France (2000)Monk-Steel, A.D., Thompson, D.J., De Beer, F.G., Janssens, M.H.A.: An investigation into the influence of longitudinal creepage on railway squeal noise due to lateral creepage. J. 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Threat captures attention, but not automatically: Top-down goals modulate attentional orienting to threat distractors

The rapid orienting of attention to potential threats has been proposed to proceed outside of top-down control. However, paradigms that have been used to investigate this have struggled to separate the rapid orienting of attention (i.e. capture) from the later disengagement of focal attention that may be subject to top-down control. Consequently, it remains unclear whether and to what extent orienting to threat is contingent on top-down goals. The current study manipulated the goal-relevance of threat distractors (spiders), whilst a strict top-down attentional set was encouraged by presenting the saliently colored target and the threat distracter simultaneously for a limited time. The goal-relevance of threatening distractors was manipulated by including a spider amongst the possible target stimuli (Experiment 1: spider/cat targets) or excluding it (Experiment 2: bird/fish targets). Orienting and disengagement were disentangled by cueing attention away from or towards the threat prior to its onset. The results indicated that the threatening spider distractors elicited rapid orienting of attention when spiders were potentially goal-relevant (Experiment 1) but did so much less when they were irrelevant to the task goal (Experiment 2). Delayed disengagement from the threat distractors was even more strongly contingent on the task goal and occurred only when a spider was a possible target. These results highlight the role of top-down goals in attentional orienting to and disengagement from threat. © 2016 The Psychonomic Society, Inc

Comparative SNP and Haplotype Analysis Reveals a Higher Genetic Diversity and Rapider LD Decay in Tropical than Temperate Germplasm in Maize

Understanding of genetic diversity and linkage disequilibrium (LD) decay in diverse maize germplasm is fundamentally important for maize improvement. A total of 287 tropical and 160 temperate inbred lines were genotyped with 1943 single nucleotide polymorphism (SNP) markers of high quality and compared for genetic diversity and LD decay using the SNPs and their haplotypes developed from genic and intergenic regions. Intronic SNPs revealed a substantial higher variation than exonic SNPs. The big window size haplotypes (3-SNP slide-window covering 2160 kb on average) revealed much higher genetic diversity than the 10 kb-window and gene-window haplotypes. The polymorphic information content values revealed by the haplotypes (0.436–0.566) were generally much higher than individual SNPs (0.247–0.259). Cluster analysis classified the 447 maize lines into two major groups, corresponding to temperate and tropical types. The level of genetic diversity and subpopulation structure were associated with the germplasm origin and post-domestication selection. Compared to temperate lines, the tropical lines had a much higher level of genetic diversity with no significant subpopulation structure identified. Significant variation in LD decay distance (2–100 kb) was found across the genome, chromosomal regions and germplasm groups. The average of LD decay distance (10–100 kb) in the temperate germplasm was two to ten times larger than that in the tropical germplasm (5–10 kb). In conclusion, tropical maize not only host high genetic diversity that can be exploited for future plant breeding, but also show rapid LD decay that provides more opportunity for selection

Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis

<p>Abstract</p> <p>Background</p> <p>Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but prescribing it requires careful attention in order to rule out contraindications to its use. Contraindications include a history of certain neurological conditions that might increase the risk of seizure and other adverse events. The precise pathophysiological mechanism by which mefloquine might predispose those with such a history to seizure remains unclear.</p> <p>Presentation of the hypothesis</p> <p>Studies have demonstrated that mefloquine at doses consistent with chemoprophylaxis accumulates at high levels in brain tissue, which results in altered neuronal calcium homeostasis, altered gap-junction functioning, and contributes to neuronal cell death. This paper reviews the scientific evidence associating mefloquine with alterations in neuronal function, and it suggests the novel hypothesis that among those with the prevalent EPM1 mutation, inherited and mefloquine-induced impairments in neuronal physiologic safeguards might increase risk of GABAergic seizure during mefloquine chemoprophylaxis.</p> <p>Testing and implications of the hypothesis</p> <p>Consistent with case reports of tonic-clonic seizures occurring during mefloquine chemoprophylaxis among those with family histories of epilepsy, it is proposed here that a new contraindication to mefloquine use be recognized for people with EPM1 mutation and for those with a personal history of myoclonus or ataxia, or a family history of degenerative neurologic disorder consistent with EPM1. Recommendations and directions for future research are presented.</p

Genetic Diversity and Linkage Disequilibrium in Chinese Bread Wheat (Triticum aestivum L.) Revealed by SSR Markers

Two hundred and fifty bread wheat lines, mainly Chinese mini core accessions, were assayed for polymorphism and linkage disequilibrium (LD) based on 512 whole-genome microsatellite loci representing a mean marker density of 5.1 cM. A total of 6,724 alleles ranging from 1 to 49 per locus were identified in all collections. The mean PIC value was 0.650, ranging from 0 to 0.965. Population structure and principal coordinate analysis revealed that landraces and modern varieties were two relatively independent genetic sub-groups. Landraces had a higher allelic diversity than modern varieties with respect to both genomes and chromosomes in terms of total number of alleles and allelic richness. 3,833 (57.0%) and 2,788 (41.5%) rare alleles with frequencies of <5% were found in the landrace and modern variety gene pools, respectively, indicating greater numbers of rare variants, or likely new alleles, in landraces. Analysis of molecular variance (AMOVA) showed that A genome had the largest genetic differentiation and D genome the lowest. In contrast to genetic diversity, modern varieties displayed a wider average LD decay across the whole genome for locus pairs with r2>0.05 (P<0.001) than the landraces. Mean LD decay distance for the landraces at the whole genome level was <5 cM, while a higher LD decay distance of 5–10 cM in modern varieties. LD decay distances were also somewhat different for each of the 21 chromosomes, being higher for most of the chromosomes in modern varieties (<5∼25 cM) compared to landraces (<5∼15 cM), presumably indicating the influences of domestication and breeding. This study facilitates predicting the marker density required to effectively associate genotypes with traits in Chinese wheat genetic resources