Auditory training changes temporal lobe connectivity in 'Wernicke's aphasia': a randomised trial

INTRODUCTION: Aphasia is one of the most disabling sequelae after stroke, occurring in 25%-40% of stroke survivors. However, there remains a lack of good evidence for the efficacy or mechanisms of speech comprehension rehabilitation. TRIAL DESIGN: This within-subjects trial tested two concurrent interventions in 20 patients with chronic aphasia with speech comprehension impairment following left hemisphere stroke: (1) phonological training using 'Earobics' software and (2) a pharmacological intervention using donepezil, an acetylcholinesterase inhibitor. Donepezil was tested in a double-blind, placebo-controlled, cross-over design using block randomisation with bias minimisation. METHODS: The primary outcome measure was speech comprehension score on the comprehensive aphasia test. Magnetoencephalography (MEG) with an established index of auditory perception, the mismatch negativity response, tested whether the therapies altered effective connectivity at the lower (primary) or higher (secondary) level of the auditory network. RESULTS: Phonological training improved speech comprehension abilities and was particularly effective for patients with severe deficits. No major adverse effects of donepezil were observed, but it had an unpredicted negative effect on speech comprehension. The MEG analysis demonstrated that phonological training increased synaptic gain in the left superior temporal gyrus (STG). Patients with more severe speech comprehension impairments also showed strengthening of bidirectional connections between the left and right STG. CONCLUSIONS: Phonological training resulted in a small but significant improvement in speech comprehension, whereas donepezil had a negative effect. The connectivity results indicated that training reshaped higher order phonological representations in the left STG and (in more severe patients) induced stronger interhemispheric transfer of information between higher levels of auditory cortex.Clinical trial registrationThis trial was registered with EudraCT (2005-004215-30, https://eudract.ema.europa.eu/) and ISRCTN (68939136, http://www.isrctn.com/)

Individual correlates of podoconiosis in areas of varying endemicity: a case-control study

BACKGROUND Podoconiosis is a non-filarial form of elephantiasis resulting in lymphedema of the lower legs. Previous studies have suggested that podoconiosis arises from the interplay of individual and environmental factors. Here, our aim was to understand the individual-level correlates of podoconiosis by comparing 460 podoconiosis-affected individuals and 707 unaffected controls. METHODS/PRINCIPAL FINDINGS This was a case-control study carried out in six kebeles (the lowest governmental administrative unit) in northern Ethiopia. Each kebele was classified into one of three endemicity levels: 'low' (prevalence 5%). A total of 142 (30.7%) households had two or more cases of podoconiosis. Compared to controls, the majority of the cases, especially women, were less educated (OR = 1.7, 95% CI = 1.3 to 2.2), were unmarried (OR = 3.4, 95% CI = 2.6-4.6) and had lower income (t = -4.4, p<0.0001). On average, cases started wearing shoes ten years later than controls. Among cases, age of first wearing shoes was positively correlated with age of onset of podoconiosis (r = 0.6, t = 12.5, p<0.0001). Among all study participants average duration of shoe wearing was less than 30 years. Between both cases and controls, people in 'high' and 'medium' endemicity kebeles were less likely than people in 'low' endemicity areas to 'ever' have owned shoes (OR = 0.5, 95% CI = 0.4-0.7). CONCLUSIONS Late use of shoes, usually after the onset of podoconiosis, and inequalities in education, income and marriage were found among cases, particularly among females. There were clustering of cases within households, thus interventions against podoconiosis will benefit from household-targeted case tracing. Most importantly, we identified a secular increase in shoe-wearing over recent years, which may give opportunities to promote shoe-wearing without increasing stigma among those at high risk of podoconiosis

Podoconiosis in East and West Gojam Zones, Northern Ethiopia

Background: Podoconiosis is a neglected tropical disease (NTD) that is prevalent in red clay soil-covered highlands of tropical Africa, Central and South America, and northern India. It is estimated that up to one million cases exist in Ethiopia. This study aimed to estimate the prevalence of podoconiosis in East and West Gojam Zones of Amhara Region in northern Ethiopia. Methodology/Principal Findings: A cross-sectional household survey was conducted in Debre Eliyas and Dembecha woredas (districts) in East and West Gojam Zones, respectively. The survey covered all 17,553 households in 20 kebeles (administrative subunits) randomly selected from the two woredas. A detailed structured interview was conducted on 1,704 cases of podoconiosis identified in the survey. Results: The prevalence of podoconiosis in the population aged 15 years and above was found to be 3.3% (95% CI, 3.2% to 3.6%). 87% of cases were in the economically active age group (15–64 years). On average, patients sought treatment five years after the start of the leg swelling. Most subjects had second (42.7%) or third (36.1%) clinical stage disease, 97.9% had mossy lesions, and 53% had open wounds. On average, patients had five episodes of acute adenolymphangitis (ALA) per year and spent a total of 90 days per year with ALA. The median age of first use of shoes and socks were 22 and 23 years, respectively. More men than women owned more than one pair of shoes (61.1% vs. 50.5%; x2 = 11.6 p = 0.001). At the time of interview, 23.6% of the respondents were barefoot, of whom about two-thirds were women. Conclusions: This study showed high prevalence of podoconiosis and associated morbidities such as ALA, mossy lesions and open wounds in northern Ethiopia. Predominance of cases at early clinical stage of podoconiosis indicates the potential for reversing the swelling and calls for disease prevention interventions

Internal and external cooling methods and their effect on body temperature, thermal perception and dexterity

© 2018 The Authors. Published by PLOS. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1371/journal.pone.0191416© 2018 Maley et al. 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. Objective The present study aimed to compare a range of cooling methods possibly utilised by occupational workers, focusing on their effect on body temperature, perception and manual dexterity. Methods Ten male participants completed eight trials involving 30 min of seated rest followed by 30 min of cooling or control of no cooling (CON) (34C, 58% relative humidity). The cooling methods utilised were: ice cooling vest (CV0), phase change cooling vest melting at 14C (CV14), evaporative cooling vest (CVEV), arm immersion in 10C water (AI), portable water-perfused suit (WPS), heliox inhalation (HE) and ice slushy ingestion (SL). Immediately before and after cooling, participants were assessed for fine (Purdue pegboard task) and gross (grip and pinch strength) manual dexterity. Rectal and skin temperature, as well as thermal sensation and comfort, were monitored throughout. Results Compared with CON, SL was the only method to reduce rectal temperature (P = 0.012). All externally applied cooling methods reduced skin temperature (P0.05). Conclusion The present study observed that ice ingestion or ice applied to the skin produced the greatest effect on rectal and skin temperature, respectively. AI should not be utilised if workers require subsequent fine manual dexterity. These results will help inform future studies investigating appropriate pre-cooling methods for the occupational worker.This project is financially supported by the US Government through the Technical Support Working Group within the Combating Terrorism Technical Support Office.Published versio

Sensory-to-motor integration during auditory repetition: a combined fMRI and lesion study.

The aim of this paper was to investigate the neurological underpinnings of auditory-to-motor translation during auditory repetition of unfamiliar pseudowords. We tested two different hypotheses. First we used functional magnetic resonance imaging in 25 healthy subjects to determine whether a functionally defined area in the left temporo-parietal junction (TPJ), referred to as Sylvian-parietal-temporal region (Spt), reflected the demands on auditory-to-motor integration during the repetition of pseudowords relative to a semantically mediated nonverbal sound-naming task. The experiment also allowed us to test alternative accounts of Spt function, namely that Spt is involved in subvocal articulation or auditory processing that can be driven either bottom-up or top-down. The results did not provide convincing evidence that activation increased in either Spt or any other cortical area when non-semantic auditory inputs were being translated into motor outputs. Instead, the results were most consistent with Spt responding to bottom up or top down auditory processing, independent of the demands on auditory-to-motor integration. Second, we investigated the lesion sites in eight patients who had selective difficulties repeating heard words but with preserved word comprehension, picture naming and verbal fluency (i.e., conduction aphasia). All eight patients had white-matter tract damage in the vicinity of the arcuate fasciculus and only one of the eight patients had additional damage to the Spt region, defined functionally in our fMRI data. Our results are therefore most consistent with the neurological tradition that emphasizes the importance of the arcuate fasciculus in the non-semantic integration of auditory and motor speech processing

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Varying efficacy of artesunate+amodiaquine and artesunate+sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in the Democratic Republic of Congo: a report of two in-vivo studies

BACKGROUND: Very few data on anti-malarial efficacy are available from the Democratic Republic of Congo (DRC). DRC changed its anti-malarial treatment policy to amodiaquine (AQ) and artesunate (AS) in 2005. METHODS: The results of two in vivo efficacy studies, which tested AQ and sulphadoxine-pyrimethamine (SP) monotherapies and AS+SP and AS+AQ combinations in Boende (Equatorial province), and AS+SP, AS+AQ and SP in Kabalo (Katanga province), between 2003 and 2004 are presented. The methodology followed the WHO 2003 protocol for assessing the efficacy of anti-malarials in areas of high transmission. RESULTS: Out of 394 included patients in Boende, the failure rates on day 28 after PCR-genotyping adjustment of AS+SP and AS+AQ were estimated as 24.6% [95% CI: 16.6-35.5] and 15.1% [95% CI: 8.6-25.7], respectively. For the monotherapies, failure rates were 35.9% [95% CI: 27.0-46.7] for SP and 18.3% [95% CI: 11.6-28.1] for AQ. Out of 207 patients enrolled in Kabalo, the failure rate on day 28 after PCR-genotyping adjustment was 0 [1-sided 95% CI: 5.8] for AS+SP and AS+AQ [1-sided 95% CI: 6.2]. It was 19.6% [95% CI: 11.4-32.7] for SP monotherapy. CONCLUSION: The finding of varying efficacy of the same combinations at two sites in one country highlights one difficulty of implementing a uniform national treatment policy in a large country. The poor efficacy of AS+AQ in Boende should alert the national programme to foci of resistance and emphasizes the need for systems for the prospective monitoring of treatment efficacy at sentinel sites in the country

Molecular basis of FIR-mediated c-myc transcriptional control

The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c-myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration.MRC Grant-in-aid U11757455

Mapping and modelling the geographical distribution and environmental limits of podoconiosis in Ethiopia

BACKGROUND Ethiopia is assumed to have the highest burden of podoconiosis globally, but the geographical distribution and environmental limits and correlates are yet to be fully investigated. In this paper we use data from a nationwide survey to address these issues. METHODOLOGY Our analyses are based on data arising from the integrated mapping of podoconiosis and lymphatic filariasis (LF) conducted in 2013, supplemented by data from an earlier mapping of LF in western Ethiopia in 2008-2010. The integrated mapping used woreda (district) health offices' reports of podoconiosis and LF to guide selection of survey sites. A suite of environmental and climatic data and boosted regression tree (BRT) modelling was used to investigate environmental limits and predict the probability of podoconiosis occurrence. PRINCIPAL FINDINGS Data were available for 141,238 individuals from 1,442 communities in 775 districts from all nine regional states and two city administrations of Ethiopia. In 41.9% of surveyed districts no cases of podoconiosis were identified, with all districts in Affar, Dire Dawa, Somali and Gambella regional states lacking the disease. The disease was most common, with lymphoedema positivity rate exceeding 5%, in the central highlands of Ethiopia, in Amhara, Oromia and Southern Nations, Nationalities and Peoples regional states. BRT modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with population density and clay content. Based on the BRT model, we estimate that in 2010, 34.9 (95% confidence interval [CI]: 20.2-51.7) million people (i.e. 43.8%; 95% CI: 25.3-64.8% of Ethiopia's national population) lived in areas environmentally suitable for the occurrence of podoconiosis. CONCLUSIONS Podoconiosis is more widespread in Ethiopia than previously estimated, but occurs in distinct geographical regions that are tied to identifiable environmental factors. The resultant maps can be used to guide programme planning and implementation and estimate disease burden in Ethiopia. This work provides a framework with which the geographical limits of podoconiosis could be delineated at a continental scale

Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics