Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial.

Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory "oddball" task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection. Analysis also revealed that memantine treatment normalized the P2 habituation effect at the follow-up visit. These findings indicate that memantine may benefit attentional processes that represent fundamental components of executive function/dysfunction, thought to comprise the core cognitive deficit in FXTAS. The results provide evidence of target engagement of memantine, as well as therapeutically relevant information that could further the development of specific cognitive or disease-modifying therapies for FXTAS

Joint modelling of longitudinal processes and time-to-event outcomes in heart failure: systematic review and exemplar examining the relationship between serum digoxin levels and mortality

Background: Joint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how and why it is being applied to heart failure research. Methods: A systematic review of major medical databases of studies which used joint modelling within heart failure alongside an exemplar; joint modelling repeat measurements of serum digoxin with all-cause mortality using data from the Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial. Results: Overall, 28 studies were included that used joint models, 25 (89%) used data from cohort studies, the remaining 3 (11%) using data from clinical trials. 21 (75%) of the studies used biomarkers and the remaining studies used imaging parameters and functional parameters. The exemplar findings show that a per unit increase of square root serum digoxin is associated with the hazard of all-cause mortality increasing by 1.77 (1.34–2.33) times when adjusting for clinically relevant covariates. Conclusion: Recently, there has been a rise in publications of joint modelling being applied to heart failure. Where appropriate, joint models should be preferred over traditional models allowing for the inclusion of repeated measures while accounting for the biological nature of biomarkers and measurement error

Long-term Evolution and Appearance of Type Iax Postgenitor Stars

Type Iax supernovae may arise from failed explosions of white dwarfs (WDs) that leave behind a bound remnant (i.e., a "postgenitor" star) that could be identified in wide field surveys. To understand their observational signatures, we simulate these WD postgenitors from shortly after explosion until they move back down the WD cooling track, and we consider several possible WD masses and explosion energies. To predict the peculiar surface abundances of the WD postgenitors, our models take into account gravitational settling and radiative levitation. We find that radiative levitation is significant at temperatures above a mass-dependent critical temperature, typically in the range T_(eff) ≈ (50–100) × 10^3 K, significantly increasing surface abundances of iron group elements. Due to enhanced iron group opacity compared to normal WDs, the postgenitor peak luminosity and cooling timescale depend sensitively on mass, with more massive WDs becoming brighter but cooling much faster. We discuss our results in light of recently discovered hypervelocity WDs with peculiar surface compositions, finding that our low-mass postgenitor models match many of their observational characteristics. Finally, we explore the effects of thermohaline diffusion, tentatively finding that it strongly suppresses abundance enhancements created by radiative levitation, but more realistic modeling is required to reach a firm conclusion

Search Engine for Antimicrobial Resistance: A Cloud Compatible Pipeline and Web Interface for Rapidly Detecting Antimicrobial Resistance Genes Directly from Sequence Data.

BACKGROUND: Antimicrobial resistance remains a growing and significant concern in human and veterinary medicine. Current laboratory methods for the detection and surveillance of antimicrobial resistant bacteria are limited in their effectiveness and scope. With the rapidly developing field of whole genome sequencing beginning to be utilised in clinical practice, the ability to interrogate sequencing data quickly and easily for the presence of antimicrobial resistance genes will become increasingly important and useful for informing clinical decisions. Additionally, use of such tools will provide insight into the dynamics of antimicrobial resistance genes in metagenomic samples such as those used in environmental monitoring. RESULTS: Here we present the Search Engine for Antimicrobial Resistance (SEAR), a pipeline and web interface for detection of horizontally acquired antimicrobial resistance genes in raw sequencing data. The pipeline provides gene information, abundance estimation and the reconstructed sequence of antimicrobial resistance genes; it also provides web links to additional information on each gene. The pipeline utilises clustering and read mapping to annotate full-length genes relative to a user-defined database. It also uses local alignment of annotated genes to a range of online databases to provide additional information. We demonstrate SEAR's application in the detection and abundance estimation of antimicrobial resistance genes in two novel environmental metagenomes, 32 human faecal microbiome datasets and 126 clinical isolates of Shigella sonnei. CONCLUSIONS: We have developed a pipeline that contributes to the improved capacity for antimicrobial resistance detection afforded by next generation sequencing technologies, allowing for rapid detection of antimicrobial resistance genes directly from sequencing data. SEAR uses raw sequencing data via an intuitive interface so can be run rapidly without requiring advanced bioinformatic skills or resources. Finally, we show that SEAR is effective in detecting antimicrobial resistance genes in metagenomic and isolate sequencing data from both environmental metagenomes and sequencing data from clinical isolates.This research was funded by GlaxoSmithKline, the Centre for Environment, Fisheries and Aquaculture Science and the Biotechnology and Biological Sciences Research Council under an industrial CASE studentship. The funder Centre for Environment, Fisheries and Aquaculture Science provided support in the form of salaries, research materials and facilities for authors DVJ and CBA, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder GlaxoSmithKline provided support in the form of salaries for author JR, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version. It was first published by PLOS at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133492

Knowledge regarding Hepatitis C among injecting drug users, Drugs: Education, Prevention and Policy,

Abstract Hepatitis C (HCV) is very prevalent among injecting drug users (IDU). Control of this infection poses a major challenge to harm reduction services. Education of all IDU regarding HCV constitutes part of the harm reduction programme. We sought to assess understanding of HCV among IDU attending an addiction treatment clinic and to identify whether or not those with increased contact with health professionals demonstrated better understanding. 105 IDU were interviewed to assess their knowledge regarding modes of transmission and chronicity of HCV infection. They had first injected an average of 10.0 years previously. Interviewees were more successful at identifying activities which carried a risk of HCV transmission than they were at identifying activities which posed no risk of infection. Over one third falsely believed that one could contract HCV infection even when injecting 'safely'. Understanding of the long term nature of HCV infection was also impaired. A group on methadone maintenance for a median period of 1.4 years failed to demonstrate significantly better knowledge than those attending for a 21-day detoxification. Those in frequent contact with a GP performed less well than those without such contact. Understanding of HCV among IDU is inadequate and must improve if primary prevention efforts are to succeed. We question the value of didactic approaches to educating IDU and call for a more experiential teaching style which may be more successful at countering prevalent misconceptions

CheapStat: An Open-Source, “Do-It-Yourself” Potentiostat for Analytical and Educational Applications

Although potentiostats are the foundation of modern electrochemical research, they have seen relatively little application in resource poor settings, such as undergraduate laboratory courses and the developing world. One reason for the low penetration of potentiostats is their cost, as even the least expensive commercially available laboratory potentiostats sell for more than one thousand dollars. An inexpensive electrochemical workstation could thus prove useful in educational labs, and increase access to electrochemistry-based analytical techniques for food, drug and environmental monitoring. With these motivations in mind, we describe here the CheapStat, an inexpensive (<$80), open-source (software and hardware), hand-held potentiostat that can be constructed by anyone who is proficient at assembling circuits. This device supports a number of potential waveforms necessary to perform cyclic, square wave, linear sweep and anodic stripping voltammetry. As we demonstrate, it is suitable for a wide range of applications ranging from food- and drug-quality testing to environmental monitoring, rapid DNA detection, and educational exercises. The device's schematics, parts lists, circuit board layout files, sample experiments, and detailed assembly instructions are available in the supporting information and are released under an open hardware license

Prevalence and Types of Drugs Used Among Hepatitis A Patients During Outbreaks Associated with Person-to-Person Transmission, Kentucky, Michigan, and West Virginia, 2016–2019

Background: People who use drugs are at increased risk for hepatitis A virus infection. Since 1996, the Advisory Committee on Immunization Practices has recommended hepatitis A vaccination for people who use drugs. Since 2016, the U.S. has experienced widespread hepatitis A outbreaks associated with person-to-person transmission. Purpose: To describe the prevalence of drug use, route of use, and drugs used among hepatitis A outbreak-associated patients. Methods: State outbreak and medical records were reviewed to describe the prevalence, type, and route of drug use among a random sample of 812 adult outbreak-associated hepatitis A patients from Kentucky, Michigan, and West Virginia during 2016–2019. Differences in drug-use status were analyzed by demographic and risk-factor characteristics using the χ2 test. Results: Among all patients, residents of Kentucky (55.6%), Michigan (51.1%), and West Virginia (60.1%) reported any drug use, respectively. Among patients that reported any drug use, methamphetamine was the most frequently reported drug used in Kentucky (42.3%) and West Virginia (42.1%); however, opioids were the most frequently reported drug used in Michigan (46.8%). Hepatitis A patients with documented drug use were more likely (p\u3c0.05) to be experiencing homelessness/unstable housing, have been currently or recently incarcerated, and be aged 18–39 years compared to those patients without documented drug use. Implications: Drug use was prevalent among person-to-person hepatitis A outbreak-associated patients, and more likely among younger patients and patients experiencing homelessness or incarceration. Increased hepatitis A vaccination coverage is critical to prevent similar outbreaks in the future

Conceptualizing Ecological Responses to Dam Removal: If You Remove It, What’s to Come?

One of the desired outcomes of dam decommissioning and removal is the recovery of aquatic and riparian ecosystems. To investigate this common objective, we synthesized information from empirical studies and ecological theory into conceptual models that depict key physical and biological links driving ecological responses to removing dams. We define models for three distinct spatial domains: upstream of the former reservoir, within the reservoir, and downstream of the removed dam. Emerging from these models are response trajectories that clarify potential pathways of ecological transitions in each domain. We illustrate that the responses are controlled by multiple causal pathways and feedback loops among physical and biological components of the ecosystem, creating recovery trajectories that are dynamic and nonlinear. In most cases, short-term effects are typically followed by longer-term responses that bring ecosystems to new and frequently predictable ecological condition, which may or may not be similar to what existed prior to impoundment

Comparative metagenomics reveals a diverse range of antimicrobial resistance genes in effluents entering a river catchment.

The aquatic environment has been implicated as a reservoir for antimicrobial resistance genes (ARGs). In order to identify sources that are contributing to these gene reservoirs, it is crucial to assess effluents that are entering the aquatic environment. Here we describe a metagenomic assessment for two types of effluent entering a river catchment. We investigated the diversity and abundance of resistance genes, mobile genetic elements (MGEs) and pathogenic bacteria. Findings were normalised to a background sample of river source water. Our results show that effluent contributed an array of genes to the river catchment, the most abundant being tetracycline resistance genes tetC and tetW from farm effluents and the sulfonamide resistance gene sul2 from wastewater treatment plant (WWTP) effluents. In nine separate samples taken across 3 years, we found 53 different genes conferring resistance to seven classes of antimicrobial. Compared to the background sample taken up river from effluent entry, the average abundance of genes was three times greater in the farm effluent and two times greater in the WWTP effluent. We conclude that effluents disperse ARGs, MGEs and pathogenic bacteria within a river catchment, thereby contributing to environmental reservoirs of ARGs.This research was funded by the Centre for Environment, Fisheries and Aquaculture Science, GlaxoSmithKline and the Biotechnology and Biological Sciences Research Council. Metagenomic sequencing was performed by the Sequencing Service and Wellcome Trust Biomedical Informatics Hub, Exeter (UK).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by IWA Publishing

Protocol for the Foot in Juvenile Idiopathic Arthritis trial (FiJIA): a randomised controlled trial of an integrated foot care programme for foot problems in JIA

&lt;b&gt;Background&lt;/b&gt;: Foot and ankle problems are a common but relatively neglected manifestation of juvenile idiopathic arthritis. Studies of medical and non-medical interventions have shown that clinical outcome measures can be improved. However existing data has been drawn from small non-randomised clinical studies of single interventions that appear to under-represent the adult population suffering from juvenile idiopathic arthritis. To date, no evidence of combined therapies or integrated care for juvenile idiopathic arthritis patients with foot and ankle problems exists. &lt;b&gt;Methods/design&lt;/b&gt;: An exploratory phase II non-pharmacological randomised controlled trial where patients including young children, adolescents and adults with juvenile idiopathic arthritis and associated foot/ankle problems will be randomised to receive integrated podiatric care via a new foot care programme, or to receive standard podiatry care. Sixty patients (30 in each arm) including children, adolescents and adults diagnosed with juvenile idiopathic arthritis who satisfy the inclusion and exclusion criteria will be recruited from 2 outpatient centres of paediatric and adult rheumatology respectively. Participants will be randomised by process of minimisation using the Minim software package. The primary outcome measure is the foot related impairment measured by the Juvenile Arthritis Disability Index questionnaire's impairment domain at 6 and 12 months, with secondary outcomes including disease activity score, foot deformity score, active/limited foot joint counts, spatio-temporal and plantar-pressure gait parameters, health related quality of life and semi-quantitative ultrasonography score for inflammatory foot lesions. The new foot care programme will comprise rapid assessment and investigation, targeted treatment, with detailed outcome assessment and follow-up at minimum intervals of 3 months. Data will be collected at baseline, 6 months and 12 months from baseline. Intention to treat data analysis will be conducted. A full health economic evaluation will be conducted alongside the trial and will evaluate the cost effectiveness of the intervention. This will consider the cost per improvement in Juvenile Arthritis Disability Index, and cost per quality adjusted life year gained. In addition, a discrete choice experiment will elicit willingness to pay values and a cost benefit analysis will also be undertaken