COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification.

Viral sequence classification has wide applications in clinical, epidemiological, structural and functional categorization studies. Most existing approaches rely on an initial alignment step followed by classification based on phylogenetic or statistical algorithms. Here we present an ultrafast alignment-free subtyping tool for human immunodeficiency virus type one (HIV-1) adapted from Prediction by Partial Matching compression. This tool, named COMET, was compared to the widely used phylogeny-based REGA and SCUEAL tools using synthetic and clinical HIV data sets (1,090,698 and 10,625 sequences, respectively). COMET's sensitivity and specificity were comparable to or higher than the two other subtyping tools on both data sets for known subtypes. COMET also excelled in detecting and identifying new recombinant forms, a frequent feature of the HIV epidemic. Runtime comparisons showed that COMET was almost as fast as USEARCH. This study demonstrates the advantages of alignment-free classification of viral sequences, which feature high rates of variation, recombination and insertions/deletions. COMET is free to use via an online interface.

Concurrent motor and cognitive function in multiple sclerosis: a motor overflow and motor stability study.

OBJECTIVE AND BACKGROUND: The interplay between motor and cognitive functions during performance of concurrent tasks is not fully understood but is known to vary depending on task characteristics and across clinical populations. Our controlled study examined how a concurrent digit span task affected a motor stability and motor overflow task in patients with multiple sclerosis (MS). METHOD: We asked 22 patients with MS and 22 matched controls to exert force on a transducer using 1 index finger at a time. We measured their motor stability (accuracy of voluntary force production) and motor overflow (involuntary force produced by the opposite, inactive finger). During half of the trials, the participants concurrently performed a digit span task. RESULTS: Overall, the patients with MS had more motor overflow and less motor stability than the controls; these measures correlated with the patients' disease severity. Adding the concurrent task affected motor stability; this relationship varied with the required level of exerted force. Motor overflow was lower during trials with the concurrent task. The concurrent task affected patients and controls similarly for both motor stability and overflow. CONCLUSIONS: This study demonstrates preserved motor function in a concurrent-task paradigm in patients with MS, and sheds further light on the relationship between attention and motor function in both the patients and controls. This research may help to inform rehabilitation for everyday life situations in which patients routinely perform cognitive and motor tasks simultaneously.

Movement planning and online control in multiple sclerosis: assessment using a Fitts law reciprocal aiming task.

OBJECTIVE: We sought to quantify subtle changes in motor control in multiple sclerosis (MS) using a Fitts law reciprocal aiming task presented on a computer touchscreen. BACKGROUND: Upper-limb motor control is impaired in MS. However, many commonly used motor assessments do not detect subtle changes in motor function or differentiate between aspects of movement such as planning and online control. Fitts law states that movement time varies as a function of task difficulty, with smaller targets and greater distances making the task more difficult. METHODS: We gave a Fitts aiming task to 22 patients with MS and 22 matched controls. We manipulated movement difficulty by changing the targets' size and distance apart. RESULTS: The patients spent a significantly longer time than the controls stationary in each target before starting the next movement, and had a lower peak velocity, suggesting deficits in movement planning. The patients also spent longer in the deceleration phase of each movement, indicating deficits in the online control of movement. CONCLUSIONS: The computerized Fitts task allows quick, easy, and sensitive measurement of subtle aspects of movement. This task should be useful in clinical and research settings for assessing MS motor symptoms, disease progression, and treatment efficacy.

Polymorphisms of HIV-2 integrase and selection of resistance to raltegravir.

BACKGROUND: Human Immunodeficiency Virus type 2 is naturally resistant to some antiretroviral drugs, restricting therapeutic options for patients infected with HIV-2. Regimens including integrase inhibitors (INI) seem to be effective, but little data on HIV-2 integrase (IN) polymorphisms and resistance pathways are available. MATERIALS AND METHODS: The integrase coding sequence from 45 HIV-2-infected, INI-naïve, patients was sequenced and aligned against the ROD (group A) or EHO (group B) reference strains and polymorphic or conserved positions were analyzed.To select for raltegravir (RAL)-resistant variants in vitro, the ROD strain was cultured under increasing sub-optimal RAL concentrations for successive rounds. The phenotype of the selected variants was assessed using an MTT assay. RESULTS: We describe integrase gene polymorphisms in HIV-2 clinical isolates from 45 patients. Sixty-seven percent of the integrase residues were conserved. The HHCC Zinc coordination motif, the catalytic triad DDE motif, and AA involved in IN-DNA binding and correct positioning were highly conserved and unchanged with respect to HIV-1 whereas the connecting residues of the N-terminal domain, the dimer interface and C-terminal LEDGF binding domain were highly conserved but differed from HIV-1. The N155 H INI resistance-associated mutation (RAM) was detected in the virus population from one ARV-treated, INI-naïve patient, and the 72I and 201I polymorphisms were detected in samples from 36 and 38 patients respectively. No other known INI RAM was detected.Under RAL selective pressure in vitro, a ROD variant carrying the Q91R+I175M mutations was selected. The Q91R and I175M mutations emerged simultaneously and conferred phenotypic resistance (13-fold increase in IC50). The Q91R+I175M combination was absent from all clinical isolates. Three-dimensional modeling indicated that residue 91 lies on the enzyme surface, at the entry of a pocket containing the DDE catalytic triad and that adding a positive charge (Gln to Arg) might compromise IN-RAL affinity. CONCLUSIONS: HIV-2 polymorphisms from 45 INI-naïve patients are described. Conserved regions as well as frequencies of HIV-2 IN polymorphisms were comparable to HIV-1. Two new mutations (Q91R and I175M) that conferred high resistance to RAL were selected in vitro, which might affect therapeutic outcome.

Characterization of inhibitory failure in Multiple Sclerosis: Evidence of impaired conflict resolution.

INTRODUCTION: Inhibitory control deficits are frequently reported in Multiple Sclerosis (MS), although it is unclear whether these deficits represent a global or process-specific failure. Notably, most models of inhibitory control recognize at least two dissociable processes, the most consistent being: (a) the inhibition of a dominant response: response suppression, and (b) the inhibition of a dominant response and initiation of a nondominant response: executive control. This study aimed to ascertain the processes underlying inhibitory failure in MS. METHOD: Twenty-three MS patients and 25 healthy controls completed a battery of commonly used inhibitory tasks, with measures from each task entered into a principal components analysis with orthogonal (varimax) rotation. RESULTS: As anticipated, two components emerged, with tasks evaluating response suppression (stop signal, go/no go) loading on a common component, and tasks evaluating executive control (Stroop, antisaccade, endogenously-cued saccade) loading on a separate common component. Composite scores were generated for each component and compared between groups. Unlike response suppression scores, executive control scores were significantly poorer for MS patients. CONCLUSIONS: Inhibitory control deficits in MS may reflect poor resolution in the context of competing processes, rather than difficulty in preventing the execution of an inappropriate response.

Executive control deficits correlate with reduced frontal white matter volume in multiple sclerosis.

Introduction: Executive control deficits are frequently reported in patients with multiple sclerosis (MS). We have previously proposed that in the context of competing automatic and volitional processes, such deficits may in part reflect poor resolution of response conflict. This study aimed to investigate the neuropathological underpinnings of executive control deficits in MS, focusing on the frontostriatal system proposed to mediate executive control. Method: Forty-one MS patients and 25 healthy controls completed measures of executive control that have previously been used to characterize deficit in MS: antisaccade and endogenously cued saccade paradigms, and the Stroop color and word test. Relationships between task performance and volumetric measures of frontal white matter, frontal gray matter, striatum, and pallidum were investigated. Results: MS participants performed significantly more poorly on the Stroop and antisaccade tasks than controls. For MS patients, higher erroneous responding on the antisaccade task was related to reduced frontal white matter volume. Conclusion: These findings suggest that loss of frontal white matter may underlie executive control deficits in MS, and provides information that may inform the development of targeted cognitive training strategies in MS.

Hepatitis C virus genotypes distribution and transmission risk factors in Luxembourg from 1991 to 2006.

AIM: To analyze the Hepatitis C virus (HCV) genotype distribution and transmission risk factors in a population of unselected patients in Luxembourg. METHODS: Epidemiological information (gender, age and transmission risks) were collected from 802 patients newly diagnosed for hepatitis C and living in Luxembourg, among whom 228 patients referred from prison. Genotyping using 5'noncoding (5'NC) sequencing was performed. We compared categorical data using the Fisher's exact F-test and odds ratios (OR) were calculated for evaluating association of HCV genotype and risk factors. RESULTS: The sex ratio was predominantly male (2.2) and individuals aged less than 40 years represented 49.6% of the population. Genotype 1 was predominant (53.4%) followed by genotype 3 (33%). Among risk factors, intravenous drug usage (IVDU) was the most frequently reported (71.4%) followed by medical-related transmission (17.6%) including haemophilia, transfusion recipients and other nosocomial reasons. Genotype 3 was significantly associated to IVDU (OR = 4.84, P < 0.0001) whereas genotype 1 was significantly associated with a medical procedure (OR = 2.42, P < 0.001). The HCV genotype distribution from inmate patients differed significantly from the rest of the population (Chi-square test with four degrees of freedom, P < 0.0001) with a higher frequency of genotype 3 (46.5% vs 27.5%) and a lower frequency of genotype 1 and 4 (44.7% vs 56.8% and 5.3% vs 9.6%, respectively). IVDU was nearly exclusively reported as a risk factor in prison. CONCLUSION: We report the first description of the HCV genotype distribution in Luxembourg. The repartition is similar to other European countries, with one of the highest European prevalence rates of genotype 3 (33%). Since serology screening became available in 1991, IVDU remains the most common way of HCV transmission in Luxembourg.

Characterising Upper Limb Movements in Huntington's Disease and the Impact of Restricted Visual Cues.

BACKGROUND: Voluntary motor deficits are a common feature in Huntington's disease (HD), characterised by movement slowing and performance inaccuracies. This deficit may be exacerbated when visual cues are restricted. OBJECTIVE: To characterize the upper limb motor profile in HD with various levels of difficulty, with and without visual targets. METHODS: Nine premanifest HD (pre-HD), nine early symptomatic HD (symp-HD) and nine matched controls completed a motor task incorporating Fitts' law, a model of human movement enabling the quantification of movement timing, via the manipulation of task difficulty (i.e., target size, and distance between targets). The task required participants to make reciprocal movements under cued and blind conditions. Dwell times (time stationary between movements), speed, accuracy and variability of movements were compared between groups. RESULTS: Symp-HD showed significantly prolonged and less consistent movement times, compared with controls and pre-HD. Furthermore, movement planning and online control were significantly impaired in symp-HD, compared with controls and pre-HD, evidenced by prolonged dwell times and deceleration times. Speed and accuracy were comparable across groups, suggesting that group differences observed in movement time, variability, dwell time and deceleration time were evident over and above simple performance measures. The presence of cues resulted in greater movement time variability in symp-HD, compared with pre-HD and controls, suggesting that the deficit in movement consistency manifested only in response to targeted movements. CONCLUSIONS: Collectively, these findings provide evidence of a deficiency in both motor planning, particularly in relation to movement timing and online control, which became exacerbated as a function of task difficulty during symp-HD stages. These variables may provide a more sensitive measure of motor dysfunction than speed and/or accuracy alone in symp-HD.

Investigating the role of the corpus callosum in regulating motor overflow in multiple sclerosis.

The corpus callosum (CC) is commonly affected in multiple sclerosis (MS), however, sensitive behavioral measures of MS-related CC pathology are lacking. The CC is considered a key structure in the mediation of a type of involuntary movement known as motor overflow. In this study, we sought to characterize the impact of CC damage on motor overflow in MS. Twenty MS participants and 20 controls performed a unilateral force production task. Motor overflow (involuntary force) in the non-active hand was measured while the active hand performed the task. CC volume and lesion load were calculated for MS participants using T2-weighted MRI. We found no group differences in motor overflow; however, motor overflow correlated significantly with MS disease severity [Expanded disability status scale (EDSS)]. CC damage (lesions and decreased volume) did not correlate with motor overflow. This study suggests that CC damage may not directly lead to changes in the regulation of motor overflow. Rather, findings support the notion that a wider network of structures may mediate the production and suppression of motor overflow.

Excessive motor overflow reveals abnormal inter-hemispheric connectivity in Friedreich ataxia.

This study sought to characterise force variability and motor overflow in 12 individuals with Friedreich ataxia (FRDA) and 12 age- and gender-matched controls. Participants performed a finger-pressing task by exerting 30 and 70 % of their maximum finger force using the index finger of the right and left hand. Control of force production was measured as force variability, while any involuntary movements occurring on the finger of the other, passive hand, was measured as motor overflow. Significantly greater force variability in individuals with FRDA compared with controls is indicative of cortico-cerebellar disruption affecting motor control. Meanwhile, significantly greater motor overflow in this group provides the first evidence of possible abnormal inter-hemispheric activity that may be attributable to asymmetrical neuronal loss in the dentate nucleus. Overall, this study demonstrated a differential engagement in the underlying default processes of the motor system in FRDA.

Bioinformatics as a driver, not a passenger, of translational biomedical research: Perspectives from the 6th Benelux bioinformatics conference.

The 6th Benelux Bioinformatics Conference (BBC11) held in Luxembourg on 12 and 13 December 2011 attracted around 200 participants, including internationally-renowned guest speakers and more than 100 peer-reviewed submissions from 3 continents. Researchers from the public and private sectors convened at BBC11 to discuss advances and challenges in a wide spectrum of application areas. A key theme of the conference was the contribution of bioinformatics to enable and accelerate translational and clinical research. The BBC11 stressed the need for stronger collaborating efforts across disciplines and institutions. The demonstration of the clinical relevance of systems approaches and of next-generation sequencing-based measurement technologies are among the existing opportunities for increasing impact in translational research. Translational bioinformatics will benefit from research models that strike a balance between the importance of protecting intellectual property and the need to openly access scientific and technological advances. The full conference proceedings are freely available at http://www.bbc11.lu.

Evaluation of saliva as an alternative matrix for monitoring plasma Zidovudine, Lamivudine and nevirapine concentrations in Rwanda.

Saliva may provide interesting advantages as matrix for compliance measurements, pharmacokinetic studies and therapeutic drug monitoring in resource limited countries. We investigated the feasibility of using saliva for compliance monitoring of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in 29 HIV-1 infected patients from Rwanda. ZDV, 3TC and NVP drug levels were quantified by an LC/MS-MS method in plasma and stimulated saliva samples and compared using Bland-Altman analysis. Seven patients demonstrated undetectable saliva ZDV levels while five out of these seven also showed no 3TC salivary concentrations. For the other samples, we observed a good agreement between salivary and plasma concentrations of each antiretroviral drug. A significant relation between the difference in saliva and plasma ZDV concentrations and the average ZDV concentration in the two matrices was deduced as follow: y = -380.15 + 1.79 x. The log saliva and plasma concentration difference of both 3TC and NVP was consistent across the range of average log concentration. Overall, we showed large agreement limits suggesting a wide inter patient variability that may result to non-reliable plasma level predictions from saliva drug measurements. Therefore, our results indicate that saliva may serve as a valuable tool only for NVP compliance testing because of its high salivary concentration.