Long-term individual retention with cenobamate in adults with focal seizures: Pooled data from the clinical development program

Objective: We determined retention on open-label cenobamate therapy in the clinical development program to assess the long-term efficacy and tolerability of adjunctive cenobamate in individuals with uncontrolled focal seizures. // Methods: Data from two randomized, controlled cenobamate studies and one open-label safety and pharmacokinetic study were pooled. Based on the percentage of participants remaining on treatment, retention rates were estimated using Kaplan-Meier survival analyses. We performed two additional analyses to assess factors contributing to retention, stratifying a robust data set (through 2 years) by cenobamate modal dose and frequently used concomitant anti-seizure medications. Cenobamate discontinuations and treatment-emergent adverse events were summarized. // Results: Data from 1844 participants were pooled: 149 from a single-dose randomized trial, 355 from a multi-dose randomized trial, and 1340 from an open-label safety and pharmacokinetic study. Most participants from randomized trials continued in open-label extensions, and pooled data represent >95% of participants exposed to cenobamate. Baseline characteristics and disease and treatment histories were similar across studies. Median duration of cenobamate exposure was 34 months, with a median modal dose of 200 mg/day. Kaplan-Meier estimates of cumulative cenobamate retention rates were 80% at 1 year and 72% at 2 years. Once participants reached the maintenance phase, retention rates were consistently high in participants receiving ≥100 mg/day cenobamate, and concomitant anti-seizure medications did not affect long-term retention. By 2 years, 535 (29%) had actually discontinued cenobamate; the most common reasons for discontinuation were adverse events (37.6%), withdrawal of consent (21.1%), and other (16.8%). // Significance: Treatment retention rates provide a proxy measure for long-term efficacy, safety, tolerability, and adherence. The consistently high retention rates we found suggest that cenobamate may be an effective and well-tolerated new treatment option for people with drug-resistant focal seizures

ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency

BACKGROUND: The herpes simplex virus type 1 (HSV-1) ICP0 protein is an E3 ubiquitin ligase, which is encoded within the HSV-1 latency-associated locus. When ICP0 is not synthesized, the HSV-1 genome is acutely susceptible to cellular repression. Reciprocally, when ICP0 is synthesized, viral replication is efficiently initiated from virions or latent HSV-1 genomes. The current study was initiated to determine if ICP0's putative role as a viral interferon (IFN) antagonist may be relevant to the process by which ICP0 influences the balance between productive replication versus cellular repression of HSV-1. RESULTS: Wild-type (ICP0(+)) strains of HSV-1 produced lethal infections in scid or rag2(-/- )mice. The replication of ICP0(- )null viruses was rapidly repressed by the innate host response of scid or rag2(-/- )mice, and the infected animals remained healthy for months. In contrast, rag2(-/- )mice that lacked the IFN-α/β receptor (rag2(-/- )ifnar(-/-)) or Stat 1 (rag2(-/- )stat1(-/-)) failed to repress ICP0(- )viral replication, resulting in uncontrolled viral spread and death. Thus, the replication of ICP0(- )viruses is potently repressed in vivo by an innate immune response that is dependent on the IFN-α/β receptor and the downstream transcription factor, Stat 1. CONCLUSION: ICP0's function as a viral IFN antagonist is necessary in vivo to prevent an innate, Stat 1-dependent host response from rapidly repressing productive HSV-1 replication. This antagonistic relationship between ICP0 and the host IFN response may be relevant in regulating whether the HSV-1 genome is expressed, or silenced, in virus-infected cells in vivo. These results may also be clinically relevant. IFN-sensitive ICP0(- )viruses are avirulent, establish long-term latent infections, and induce an adaptive immune response that is highly protective against lethal challenge with HSV-1. Therefore, ICP0(- )viruses appear to possess the desired safety and efficacy profile of a live vaccine against herpetic disease

Do front-of-pack ‘green labels’ increase sustainable food choice and willingness-to-pay in U.K. consumers?

Aim: In a series of pre-registered online studies, we aimed to elucidate the magnitude of the effect of general sustainability labels on U.K. consumers’ food choices. Methods: Four labels were displayed: ‘Sustainably sourced’, ‘Locally sourced’, ‘Environmentally friendly’, and ‘Low greenhouse gas emissions’. To ensure reliable results, contingency valuation elicitation was used alongside a novel analytical approach to provide a triangulation of evidence: Multilevel-modelling compared each label vs. no-label; Poisson-modelling compared label vs. label. Socioeconomic status, environmental awareness, health motivations, and nationalism/patriotism were included in our predictive models. Results: Exp.1 Multilevel-modelling (N = 140) showed labelled products were chosen 344% more than non-labelled and consumers were willing-to-pay ∼£0.11 more, although no difference between label types was found. Poisson-modelling (N = 735) showed consumers chose Sustainably sourced and Locally sourced labels ∼20% more often but were willing-to-pay ∼£0.03 more only for Locally sourced products. Exp.2 was a direct replication. Multilevel-modelling (N = 149) showed virtually identical results (labels chosen 344% more, willingness-to-pay ∼£0.10 more), as did Poisson-modelling (N = 931) with Sustainably sourced and Locally sourced chosen ∼20% more and willingness-to-pay ∼£0.04 more for Locally sourced products. Environmental concern (specifically the ‘propensity to act’) was the only consistent predictor of preference for labelled vs. non-labelled products. Conclusions: Findings suggest front-of-pack ‘green labels’ may yield substantive increases in consumer choice alongside relatively modest increases in willingness-to-pay for environmentally-sustainable foods. Specifically, references to ‘sustainable’ or ‘local’ sourcing may have the largest impact

From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein

Perceived weight-related stigma, loneliness, and mental wellbeing during COVID-19 in people with obesity: A cross-sectional study from ten European countries

Background: Increased weight-related stigma during the COVID-19 pandemic has amplified the need to minimise the impacts on mental wellbeing. We investigated the relationship between the perceived changes in the representation of obesity in the media and mental wellbeing during the pandemic in a sample of people with obesity across 10 European countries. We also investigated the potential moderating effect of loneliness. Methods: Between September to December 2020 during the COVID-19 pandemic, participants reported data on demographics, mental wellbeing (measured by World Health Organisation Five Wellbeing Index and Patient Health Questionaire-4), loneliness (measured by De Jong Gierveld short scale), and perceived change in the representation of obesity in media (measured by a study-specific question) using the online, cross-sectional EURopean Obesity PatiEnt pANdemic Survey (EUROPEANS). Data were analysed using linear mixed-effects models, controlling for age, gender, body mass index, and shielding status, with random incept for country. Results: The survey was completed by 2882 respondents. Most identified as female (56%) and reported their ethnicity as White or White-mix (92%). The total sample had a mean age of 41 years and a BMI of 35.4 kg/m2. During the peak of the pandemic, compared to pre-pandemic, perceiving more negative representation of people with obesity on social media was associated with worse psychological distress, depression, and wellbeing. Perceiving more positive representation, compared to no change in representation, of people with obesity on television was associated with greater wellbeing, yet also higher psychological distress and anxiety. Loneliness, as a moderator, explained ≤0.3% of the variance in outcomes in any of the models. Conclusions: Perceiving negative representation of obesity on social media was associated with poorer mental wellbeing outcomes during the pandemic; positive representation on television was associated with both positive and negative mental wellbeing outcomes. We encourage greater media accountability when representing people with obesity

Spike pattern recognition by supervised classification in low dimensional embedding space

© The Author(s) 2016. This article is published with open access at Springerlink.com under the terms of the Creative Commons Attribution License 4.0, (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Epileptiform discharges in interictal electroencephalography (EEG) form the mainstay of epilepsy diagnosis and localization of seizure onset. Visual analysis is rater-dependent and time consuming, especially for long-term recordings, while computerized methods can provide efficiency in reviewing long EEG recordings. This paper presents a machine learning approach for automated detection of epileptiform discharges (spikes). The proposed method first detects spike patterns by calculating similarity to a coarse shape model of a spike waveform and then refines the results by identifying subtle differences between actual spikes and false detections. Pattern classification is performed using support vector machines in a low dimensional space on which the original waveforms are embedded by locality preserving projections. The automatic detection results are compared to experts’ manual annotations (101 spikes) on a whole-night sleep EEG recording. The high sensitivity (97 %) and the low false positive rate (0.1 min−1), calculated by intra-patient cross-validation, highlight the potential of the method for automated interictal EEG assessment.Peer reviewedFinal Published versio

A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese

<p>Abstract</p> <p>Background</p> <p>The human MutY homolog (<it>hMYH</it>), a DNA glycolsylase involved in the excision repair of oxidative DNA damage, is currently studied in colorectal cancer (CRC). We previously demonstrated a haplotype variant c.53C>T/c.74G>A of <it>hMYH </it>(T/A) increasing the risk for gastric cancer in Chinese. However, most investigations on correlation between <it>hMYH </it>and CRC are conducted in Western countries and the underlying mechanism has been poorly understood.</p> <p>Methods</p> <p>To determine whether the haplotype T/A variant of <it>hMYH </it>was related to colorectal carcinogenesis, we performed a case-control study in 138 colorectal cancer (CRC) patients and 343 healthy controls in a Chinese population. Furthermore, the C/G for wild-type, C/A or T/G for single base variant and T/A for haplotype variant <it>hMYH </it>cDNAs with a flag epitope tag were cloned into pcDNA3.1+ vector and transfected into cos-7 cell line. Their subcellular localizations were determined by immunofluorescence assay.</p> <p>Results</p> <p>It was found that the frequency of haplotype variant allele was statistically higher in CRC patients than that in controls (<it>P </it>= 0.02, odds ratio = 5.06, 95% confidence interval = 1.26 – 20.4). Similarly, significant difference of heterozygote frequency was indicated between the two groups (<it>P </it>= 0.019), while no homozygote was found. In addition, immunofluorescence analysis showed that hMYH protein with haplotype T/A variation presented in both nucleus and mitochondria, in contrast to the wild-type protein only converging in mitochondria. However, neither of the single missense mutations alone changed the protein subcelluar localization.</p> <p>Conclusion</p> <p>Although preliminarily, these results suggest that: the haplotype variant allele of <it>hMYH </it>leads to a missense protein, which partly affects the protein mitochondrial transportation and results as nuclear localization. This observation might be responsible for the increased susceptibility to cancers, including CRC, in Chinese.</p

Direct application of plasmid DNA containing type I interferon transgenes to vaginal mucosa inhibits HSV-2 mediated mortality

The application of naked DNA containing type I interferon (IFN) transgenes is a promising potential therapeutic approach for controlling chronic viral infections. Herein, we detail the application of this approach that has been extensively used to restrain ocular HSV-1 infection, for antagonizing vaginal HSV-2 infection. We show that application of IFN-α1, -α5, and –β transgenes to vaginal mouse lumen 24 hours prior to HSV-2 infection reduces HSV-2 mediated mortality by 2.5 to 3-fold. However, other type I IFN transgenes (IFN- α4, -α5, -α6, and –α9) are non effectual against HSV-2. We further show that the efficacy of IFN-α1 transgene treatment is independent of CD4+ T lymphocytes. However, in mice depleted of CD8+ T lymphocytes, the ability of IFN-α1 transgene treatment to antagonize HSV-2 was lost

Opposite polarities of ENSO drive distinct patterns of coral bleaching potentials in the southeast Indian Ocean.

Episodic anomalously warm sea surface temperature (SST) extremes, or marine heatwaves (MHWs), amplify ocean warming effects and may lead to severe impacts on marine ecosystems. MHW-induced coral bleaching events have been observed frequently in recent decades in the southeast Indian Ocean (SEIO), a region traditionally regarded to have resilience to global warming. In this study, we assess the contribution of El Niño-Southern Oscillation (ENSO) to MHWs across the mostly understudied reefs in the SEIO. We find that in extended summer months, the MHWs at tropical and subtropical reefs (divided at ~20°S) are driven by opposite ENSO polarities: MHWs are more likely to occur at the tropical reefs during eastern Pacific El Niño, driven by enhanced solar radiation and weaker Australian Monsoon, some likely alleviated by positive Indian Ocean Dipole events, and at the subtropical reefs during central Pacific La Niña, mainly caused by increased horizontal heat transport, and in some cases reinforced by local air-sea interactions. Madden-Julian Oscillations (MJO) also modulate the MHW occurrences. Projected future increases in ENSO and MJO intensity with greenhouse warming will enhance thermal stress across the SEIO. Implementing forecasting systems of MHWs can be used to anticipate future coral bleaching patterns and prepare management responses

Quantitative EEG findings in patients with acute, brief depression combined with other fluctuating psychiatric symptoms: a controlled study from an acute psychiatric department

<p>Abstract</p> <p>Background</p> <p>Patients with brief depressive episodes and concurrent rapidly fluctuating psychiatric symptoms do not fit current diagnostic criteria and they can be difficult to diagnose and treat in an acute psychiatric setting. We wanted to study whether these patients had signs of more epileptic or organic brain dysfunction than patients with depression without additional symptomatology.</p> <p>Methods</p> <p>Sixteen acutely admitted patients diagnosed with a brief depressive episode as well as another concurrent psychiatric diagnosis were included. Sixteen patients with major depression served as controls. Three electroencephalographic studies (EEG) were visually interpreted and the background activity was also analysed with quantitative electroencephalography (QEEG).</p> <p>Results</p> <p>The group with brief depression and concurrent symptoms had multiple abnormal features in their standard EEG compared to patients with major depression, but they did not show significantly more epileptiform activity. They also had significantly higher temporal QEEG delta amplitude and interhemispheric temporal delta asymmetry.</p> <p>Conclusion</p> <p>Organic brain dysfunction may be involved in the pathogenesis of patients with brief depressive episodes mixed with rapidly fluctuating psychiatric symptoms. This subgroup of depressed patients should be investigated further in order to clarify the pathophysiology and to establish the optimal evaluation scheme and treatment in an acute psychiatric setting.</p