Is Pitolisant Effective in Reducing Excessive Daytime Sleepiness and Cataplexy in Adults with Narcolepsy?

Objective: The objective of this selective EBM review is to determine whether or not pitolisant is effective in reducing excessive daytime sleepiness and cataplexy in adults with narcolepsy. Study Design: Review of two randomized control trials (RCTs) published in 2013 and 2017, and one prospective, placebo-controlled, single-blind study published in 2008. Data Sources: All articles were published in English and taken from peer-reviewed journals, which were found using the PubMed database. Outcomes Measured: The outcomes of investigation measured include excessive daytime sleepiness (EDS) assessed by change in Epworth Sleepiness Scale (ESS) score, and cataplexy rate calculated from recorded cataplexy attacks in patients’ sleep diaries. Results: Dauvilliers, et al. found pitolisant was more effective in reducing mean ESS scores from baseline compared to placebo (-5.8 vs -3.4; p=0.024). A decrease in ESS score indicates improved EDS. Also, in post-hoc analyses, Dauvilliers et al. found that pitolisant was superior to placebo in reducing daily cataplexy rate from baseline (0.38 vs 0.92; p=0.034). Szakacs, et al. found pitolisant to be effective in reducing weekly cataplexy rate (WCR) by 75% from baseline compared to placebo (38% decrease in WCR), p \u3c0.0001; they also report a significant decrease in ESS score from baseline in the pitolisant group compared with placebo (-5.4 vs -1.9; p= 0.0001). In a single-blind, placebo-controlled, prospective study, Lin et al. found that tiprolisant (currently called pitolisant) showed a significant reduction in ESS score from baseline compared to placebo (5.9 vs 1.0; p\u3c0.001). Conclusions: Pitolisant was shown to be efficacious in reducing EDS and cataplexy in adults with narcolepsy

Fractional Chern insulator edges and layer-resolved lattice contacts

Fractional Chern insulators (FCIs) realized in fractional quantum Hall systems subject to a periodic potential are topological phases of matter for which space group symmetries play an important role. In particular, lattice dislocations in an FCI can host topology-altering non-Abelian topological defects, known as genons. Genons are of particular interest for their potential application to topological quantum computing. In this work, we study FCI edges and how they can be used to detect genons. We find that translation symmetry can impose a quantized momentum difference between the edge electrons of a partially-filled Chern band. We propose {\it layer-resolved lattice contacts}, which utilize this momentum difference to selectively contact a particular FCI edge electron. The relative current between FCI edge electrons can then be used to detect the presence of genons in the bulk FCI. Recent experiments have demonstrated graphene is a viable platform to study FCI physics. We describe how the lattice contacts proposed here could be implemented in graphene subject to an artificial lattice, thereby outlining a path forward for experimental dectection of non-Abelian topological defects.Comment: 5+7 pages, 10 figures, v2: modified figure

Mechanisms of action of hESC-secreted proteins that enhance human and mouse myogenesis.

Adult stem cells grow poorly in vitro compared to embryonic stem cells, and in vivo stem cell maintenance and proliferation by tissue niches progressively deteriorates with age. We previously reported that factors produced by human embryonic stem cells (hESCs) support a robust regenerative capacity for adult and old mouse muscle stem/progenitor cells. Here we extend these findings to human muscle progenitors and investigate underlying molecular mechanisms. Our results demonstrate that hESC-conditioned medium enhanced the proliferation of mouse and human muscle progenitors. Furthermore, hESC-produced factors activated MAPK and Notch signaling in human myogenic progenitors, and Delta/Notch-1 activation was dependent on MAPK/pERK. The Wnt, TGF-β and BMP/pSmad1,5,8 pathways were unresponsive to hESC-produced factors, but BMP signaling was dependent on intact MAPK/pERK. c-Myc, p57, and p18 were key effectors of the enhanced myogenesis promoted by the hECS factors. To define some of the active ingredients of the hESC-secretome which may have therapeutic potential, a comparative proteomic antibody array analysis was performed and identified several putative proteins, including FGF2, 6 and 19 which as ligands for MAPK signaling, were investigated in more detail. These studies emphasize that a youthful signaling of multiple signaling pathways is responsible for the pro-regenerative activity of the hESC factors

Integrating invasion and disease in the risk assessment of live bird trade.

AimInternational trade in plants and animals generates significant economic benefits. It also leads to substantial unintended impacts when introduced species become invasive, causing environmental disturbance or transmitting diseases that affect people, livestock, other wildlife or the environment. Policy responses are usually only implemented after these species become established and damages are already incurred. International agreements to control trade are likewise usually based on selection of species with known impacts. We aim to further develop quantitative invasive species risk assessment for bird imports and extend the tool to explicitly address disease threats.LocationUnited States of America.MethodsWe use a two-step approach for rapid risk assessment based on the expected biological risks due to both the environmental and health impact of a potentially invasive wildlife species in trade. We assess establishment probability based on a model informed by historical observations and then construct a model of emerging infectious disease threat based on economic and ecological characteristics of the exporting country.ResultsWe illustrate how our rapid assessment tool can be used to identify high-priority species for regulation based on a combination of the threat they pose for becoming established and vectoring emerging infectious diseases.Main conclusionsOur approach can be executed for a species in a matter of days and is nested in an economic decision-making framework for determining whether the biological risk is justified by trade benefits

hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding.

This work builds upon our findings that proteins secreted by hESCs exhibit pro-regenerative activity, and determines that hESC-conditioned medium robustly enhances the proliferation of both muscle and neural progenitor cells. Importantly, this work establishes that it is the proteins that bind heparin which are responsible for the pro-myogenic effects of hESC-conditioned medium, and indicates that this strategy is suitable for enriching the potentially therapeutic factors. Additionally, this work shows that hESC-secreted proteins act independently of the mitogen FGF-2, and suggests that FGF-2 is unlikely to be a pro-aging molecule in the physiological decline of old muscle repair. Moreover, hESC-secreted factors improve the viability of human cortical neurons in an Alzheimers disease (AD) model, suggesting that these factors can enhance the maintenance and regeneration of multiple tissues in the aging body

Quarkonium states in a complex-valued potential

We calculate quarkonium binding energies using a realistic complex-valued potential for both an isotropic and anisotropic quark-gluon plasma. We determine the disassociation temperatures of the ground and first excited states considering both the real and imaginary parts of the binding energy. We show that the effect of momentum-space anisotropy is smaller on the imaginary part of the binding energy than on the real part of the binding energy. In the case that one assumes an isotropic plasma, we find disassociation temperatures for the J/psi, Upsilon and chi_b of 1.6 T_c, 2.8 T_c, and 1.5 T_c, respectively. We find that a finite oblate momentum-space anisotropy increases the disassociation temperature for all states considered and results in a splitting of the p-wave states associated with the chi_b first excited state of bottomonium.Comment: 23 pages, 9 figures; v4: subtraction of V_infinity corrected to only subtract Re[V_infinity

Lessons Learned from a Nontraditional Sports Program: CrossFit Kids for Youth at Risk

Offering youth, especially youth at risk, access to something different has the opportunity to allow participants to discover new passions and interests. A nontraditional sports program was offered to middle school students who were members of the local Boys and Girls Club during the 2015–2016 academic year. Identifying a program focusing on CrossFit was valuable because CrossFit Kids programming is geared to develop the whole child addressing health and lifestyle choices and social responsibility. The purpose of this paper is to describe the program, examine what worked and did not work, and note what changes were made based on the outcomes. Overall, the program proved to be valuable for the participants. Success was found when the participants’ voices were used to inform adjustments to the program based on their needs instead of following pre-defined, fixed outcomes

Motor Timing Intraindividual Variability in Amnestic Mild Cognitive Impairment and Cognitively Intact Elders at Genetic Risk for Alzheimer’s Disease

Introduction: Intraindividual variability (IIV) in motor performance has been shown to predict future cognitive decline. The apolipoprotein E-epsilon 4 (APOE-ε4) allele is also a well-established risk factor for memory decline. Here, we present novel findings examining the influence of the APOE-ε4 allele on the performance of asymptomatic healthy elders in comparison to individuals with amnestic MCI (aMCI) on a fine motor synchronization, paced finger-tapping task (PFTT). Method: Two Alzheimer’s disease (AD) risk groups, individuals with aMCI (n = 24) and cognitively intact APOE-ε4 carriers (n = 41), and a control group consisting of cognitively intact APOE-ε4 noncarriers (n = 65) completed the Rey Auditory Verbal Learning Test and the PFTT, which requires index finger tapping in synchrony with a visual stimulus (interstimulus interval = 333 ms). Results: Motor timing IIV, as reflected by the standard deviation of the intertap interval (ITI), was greater in the aMCI group than in the two groups of cognitively intact elders; in contrast, all three groups had statistically equivalent mean ITI. No significant IIV differences were observed between the asymptomatic APOE-ε4 carriers and noncarriers. Poorer episodic memory performance was associated with greater IIV, particularly in the aMCI group. Conclusions: Results suggest that increased IIV on a fine motor synchronization task is apparent in aMCI. This IIV measure was not sensitive in discriminating older asymptomatic individuals at genetic risk for AD from those without such a genetic risk. In contrast, episodic memory performance, a well-established predictor of cognitive decline in preclinical AD, was able to distinguish between the two cognitively intact groups based on genetic risk

Physical Activity Reduces Hippocampal Atrophy in Elders at Genetic Risk for Alzheimer\u27s Disease

We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer\u27s disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories

Using Machine Learning to Uncover Hidden Heterogeneities in Survey Data

Survey responses in public health surveys are heterogeneous. The quality of a respondent’s answers depends on many factors, including cognitive abilities, interview context, and whether the interview is in person or self-administered. A largely unexplored issue is how the language used for public health survey interviews is associated with the survey response. We introduce a machine learning approach, Fuzzy Forests, which we use for model selection. We use the 2013 California Health Interview Survey (CHIS) as our training sample and the 2014 CHIS as the test sample. We found that non-English language survey responses differ substantially from English responses in reported health outcomes. We also found heterogeneity among the Asian languages suggesting that caution should be used when interpreting results that compare across these languages. The 2013 Fuzzy Forests model also correctly predicted 86% of good health outcomes using 2014 data as the test set. We show that the Fuzzy Forests methodology is potentially useful for screening for and understanding other types of survey response heterogeneity. This is especially true in high-dimensional and complex surveys