Next generation sequencing sheds light on the natural history of hepatitis C infection in patients that fail treatment

Background and rationale of the study: High rates of sexually-transmitted infection and reinfection with hepatitis C (HCV) have recently been reported in HIV-infected men who have sex with men and reinfection has also been described in monoinfected injecting drug users. The diagnosis of reinfection has traditionally been based on direct Sanger sequencing of samples pre and post-treatment, but not on more sensitive deep sequencing techniques. We studied viral quasispecies dynamics in patients who failed standard of care therapy in a high-risk HIV-infected cohort of patients with early HCV infection to determine whether treatment failure was associated with reinfection or recrudescence of pre-existing infection. Paired sequences (pre- and post- treatment) were analysed. The HCV E2 hypervariable region-1 was amplified using nested RT-PCR with indexed genotype-specific primers and the same products were sequenced using both Sanger and 454 pyrosequencing approaches. Results: Of 99 HIV-infected patients with acute HCV treated with 24-48 weeks of pegylated interferon alpha and ribavirin, 15 failed to achieve a sustained virological response (6 relapsed, 6 had a null response and 3 had a partial response). Using direct sequencing, 10/15 patients (66%) had evidence of a previously undetected strain post-treatment; in many studies, this is interpreted as reinfection. However, pyrosequencing revealed that 15/15 (100%) of patients had evidence of persisting infection. 6/15 (40%) patients had evidence of a previously undetected variant present in the post-treatment sample in addition to a variant that was detected at baseline. This could represent superinfection or a limitation of the sensitivity of pyrosequencing. Conclusion: In this high-risk group, the emergence of new viral strains following treatment failure is most commonly associated with emerging dominance of pre-existing minority variants rather than re-infection. Superinfection may occur in this cohort but reinfection is over-estimated by Sanger sequencing. (Hepatology 2014;

Electroencephalographic event-related potentials during social interactions in people with symptoms of major depression and social anxiety

Social interactions are severely impaired in major depression and social anxiety. Social interactions associated with fairness have been studied using the Ultimatum Game (UG). In the UG, the responder receives an offer from a proposer about how to divide a sum of money. If the responder accepts the offer, both accumulate the money. If the responder rejects the offer, both accumulates nothing. The UG is comprised by fair (the responder is offered between 40-50% of the total amount of the offer), medium (the responder is offered between 27-33%) and unfair offers (the responder is offered between 18-23%). Previous studies have reported that at least two event-related potentials (ERPs) are modulated by fairness during the UG: the Medial Frontal Negativity (MFN) and the Late Positive Potential/P300 (LPP/P300). To our knowledge, there are no studies analysing ERPs in the UG in major depression and/or social anxiety. We aimed to study the MFN, the LPP/P300, the behavior and the emotions experienced during the UG in healthy volunteers (Control group, n = 72) and volunteers with symptoms of major depression and/or social anxiety (MD/SA group, n = 63). As expected, we found that the rejection of offers increased as the unfairness increased. Also, the medium offers were associated with longer reaction times than unfair offers, and in turn unfair offers were associated with longer reaction times than fair offers. In addition, participants reported less positive emotions and more negative emotions as the unfairness increased. Interestingly, in comparison with the Control group, the MD/SA group reported feeling more sadness in all offers, and specially in medium and unfair offers. The MFN was associated with more negative mean amplitudes in medium and unfair offers than in fair offers. This component would be modulated by the negative emotional/motivational impact caused by unfairness. Another plausible interpretation is that the volunteers would expect fair offers during the task, and that the unexpected medium and unfair offers would be associated with error predictions that would evoke the MFN. Interestingly, our results showed a borderline main effect of group in the MFN, suggesting that this component was associated with more negative mean amplitudes in the MD/SA group in comparison with the Control group, across all offers. This effect would be associated with enhanced negative emotions experienced during all levels of fairness during the UG in the MD/SA group, in comparison to controls. In addition, the LPP/P300 was associated with more positive mean amplitudes in fair offers in comparison with unfair offers, and with more positive mean amplitudes in unfair offers in comparison with medium offers. This result would indicate that fair offers would be associated with more arousal than unfair and medium offers, and that in turn unfair offers would be associated with more arousal than medium offers. An alternative interpretation is that the LPP/P300 would be modulated by the conflict associated with the decision-making of each level of fairness. In this line, the LPP/P300 would be more positive in fair, less conflictive offers in comparison with unfair and medium offers. In turn, this component would be more positive in unfair offers in comparison with medium offers, given that the medium offers are the most conflicting. Of note, the LPP/P300 was associated with more negative mean amplitudes in the MD/SA group in comparison with the Control group across all offers. This result could be related to less arousal and/or motivation in the MD/SA group in comparison with the Control group. Alternatively, this effect could be related to less attentional resources available to allocate to the task in the MD/SA group in comparison with controls. The lack of attentional resources in the MD/SA group could be due to the activation of other cognitive processes, such as rumination, which would compete for the cognitive resources available. Another interpretation is that this effect could be related to higher levels of conflict experienced during all offers by the MD/SA group. We aim to contribute to the understanding of social functioning and the neural basis associated with these processes in major depression and social anxiety.Las interacciones sociales se encuentran severamente afectadas en la depresión mayor y en la ansiedad social. Ciertos procesos relacionados a interacciones sociales justas e injustas se han estudiado utilizando el Ultimatum Game (UG). Durante el UG, el responder recibe ofertas de un proposer acerca de cómo dividir una cantidad de dinero. Si el responder acepta la oferta, ambos acumulan el dinero. Si el responder rechaza la oferta, ninguno acumulan nada. Durante el UG hay ofertas justas (al responder le ofrecen entre el 40-50% del total), medias (le ofrecen 27-33%) e injustas (le ofrecen 18-23%). Se ha reportado que al menos dos potenciales relacionados a eventos (ERPs, por la sigla en inglés para Event-Related Potentials) son modulados por la justicia durante el UG: el Medial Frontal Negativity (MFN) y el Late Positive Potential/P300 (LPP/P300). A nuestro conocimiento, no hay estudios que analicen ERPs durante el UG en depresión mayor y/o ansiedad social. Este proyecto tuvo como objetivo estudiar el MFN, el LPP/P300, el comportamiento y las emociones experimentadas durante el UG en personas sin historia de trastornos mentales (grupo Control, n = 72) y personas con síntomas de depresión mayor y/o ansiedad social (grupo MD/SA, n = 63). Como era esperado, la tasa de rechazo aumentó a medida que aumentaba la injusticia. Además, los tiempos de reacción fueron mayores en las ofertas medias en comparación a las injustas, y mayores en las ofertas injustas en comparación a las justas. Asimismo, los participantes reportaron más emociones negativas y menos emociones positivas a medida que aumentaba la injusticia. Cabe señalar que el grupo MD/SA reportó mayores niveles de tristeza en todas las ofertas, y especialmente en las ofertas medias e injustas. Además, el MFN se asoció a una amplitud media más negativa en las ofertas medias e injustas en comparación a las justas, lo que reflejaría el impacto emocional/motivacional negativo causado por la injusticia. Otra explicación posible es que los voluntarios esperarían recibir ofertas justas durante el UG, y que las ofertas medias e injustas inesperadas se asociarían a un error de predicción que modularía el MFN. Cabe destacar que se encontró una tendencia en el efecto principal de grupo en el MFN, sugiriendo que, en todas las ofertas, el MFN estaría asociado a una amplitud media más negativa en el grupo MD/SA en comparación al grupo Control. Este efecto estaría relacionado con emociones negativas acentuadas durante todas las ofertas en el grupo MD/SA en comparación al grupo Control. Asimismo, el LPP/P300 se asoció a una amplitud media más positiva durante ofertas justas en comparación a injustas, y con una amplitud media más positiva durante ofertas injustas en comparación a medias. Este resultado indicaría que las ofertas justas se asociarían con mayores niveles de arousal en comparación a las ofertas injustas y medias, y que las ofertas injustas se asociarían a mayores niveles de arousal que las ofertas medias. Una explicación alternativa es que el LPP/P300 sería modulado por el nivel de conflicto en la toma de decisiones. En este sentido, el LPP/P300 aparecería más positivo en las ofertas justas, que son las menos conflictivas, en comparación a ofertas injustas y medias. A su vez, el LPP/P300 se asociaría a amplitudes medias más negativas en las ofertas medias, dado que son las más conflictivas, en comparación a justas e injustas. Cabe resaltar que el LPP/P300 se asoció con una amplitud media más negativa en el grupo MD/SA que en el grupo Control en todas las ofertas. Este resultado podría estar asociado a menores niveles de arousal y/o motivación en el grupo MD/SA en comparación al grupo Control. Alernativamente, este efecto podría estar asociado a menores recursos atencionales disponibles para asignar a la tarea en el grupo MD/SA en comparación al grupo Control. Esto podría deberse a la actividad de otros procesos cognitivos que consumirían recursos cognitivos, como por ejemplo, rumia. Otra interpretación es que este efecto podría deberse a mayores niveles de conflicto experimentado en todas las ofertas en el grupo MD/SA. Esperamos contribuir al entendimiento del funcionamiento social y de las bases neurales asociadas a estos procesos en la depresión mayor y la ansiedad social

A U-Net Deep Learning Framework for High Performance Vessel Segmentation in Patients With Cerebrovascular Disease

Brain vessel status is a promising biomarker for better prevention and treatment in cerebrovascular disease. However, classic rule-based vessel segmentation algorithms need to be hand-crafted and are insufficiently validated. A specialized deep learning method-the U-net -is a promising alternative. Using labeled data from 66 patients with cerebrovascular disease, the U-net framework was optimized and evaluated with three metrics: Dice coefficient, 95% Hausdorff distance (95HD) and average Hausdorff distance (AVD). The model performance was compared with the traditional segmentation method of graph-cuts. Training and reconstruction was performed using 2D patches. A full and a reduced architecture with less parameters were trained. We performed both quantitative and qualitative analyses. The U-net models yielded high performance for both the full and the reduced architecture: A Dice value of similar to 0.88, a 95HD of similar to 47 voxels and an AVD of similar to 0.4 voxels. The visual analysis revealed excellent performance in large vessels and sufficient performance in small vessels. Pathologies like cortical laminar necrosis and a rete mirabile led to limited segmentation performance in few patients. The U-net outperfomed the traditional graph-cuts method (Dice similar to 0.76, 95HD similar to 59, AVD similar to 1.97). Our work highly encourages the development of clinically applicable segmentation tools based on deep learning. Future works should focus on improved segmentation of small vessels and methodologies to deal with specific pathologies

Effect of a Legume (Arachis pintoi) on the Regrowth and Mineral Nutrition of Associated Pangola grass (Digitaria decumbens)

The effect of a companion legume (Arachis pintoi) on the growth and nitrogen nutrition of an associated grass (Di\u27gitaria decumbems) was studied during 2 regrowth periods. Digitaria growth was expressed as a function of the cumulative absorded PAR (photosynthetically active radiation) i.e., by using the radiation-use efficiency concept. For this purpose, PAR intercepted by both the pure and mixed swards was estimated by using a radiative transfer model. Nitrogen nutrition status of Digitaria was characterised by the relation between N uptake and dry matter production. Results show a close agreement between N nutrition level and radiation-use efficiency of the grass. As the result of the seasonal change of environmental N supply, radiation-use efficiency differences between the 2 growth periods were large. On tile other hnlld, radiation-use efficiency • and nitrogen nutrition did not show any significant difference between pure and mixed grasses

Connectivity analysis of subthalamic and pallidal Deep Brain Stimulation in Parkinson’s Disease

Die tiefe Hirnstimulation (THS) ist für Patient*innen mit fortgeschrittenem idiopathischen Parkinson-Syndroms (IPS) eine etablierte Therapieoption, um Kardinalsymptome des IPS sowie dopamin-induzierte Dyskinesien und Symptomfluktuationen zu verringern. Anatomische Zielstrukturen für eine Implantation der Elektroden sind der subthalamische Nucleus (STN) und der Globus Pallidus internus (GPi). Die Effektivität und der detaillierte Wirkmechanismus der THS in diesen beiden Kerngebieten ist nicht abschließend geklärt. Eine eindeutige Präferenz hinsichtlich des Zielgebiets konnte trotz mehrere randomisierter Doppelblind-Studien nicht ermittelt werden. Die vorliegende Arbeit hat das Ziel, anhand von Konnektivitätsanalysen die Wirksamkeit der THS in zwei Kohorten von 94 Patient*innen mit einer STN- Stimulation einerseits und bei 28 Patient*innen mit einer GPi-Stimulation andererseits retrospektiv zu vergleichen. Pro Patient*in wurden je zwei Elektroden in entweder das bilaterale STN- oder das GPi- Zielgebiet implantiert. Die Hypothese ist der Nachweis eines gemeinsamen funktionel-len Netzwerks, welches durch die THS unterschiedlicher Kerngebiete moduliert wird. Durch den Vergleich der prä- und postoperativen Bildgebung wurde zunächst die Lokalisation jedes Elektrodenpaars rekonstruiert. Die protokollierten Stimulationsparameter wurden genutzt, um Stimulationsvolumina zu berechnen. Anhand eines funktionellen Konnektoms wurde schließlich in sämtlichen Patient*innen das funktionelle Verbindungsprofil dieser bilateralen Stimulationsvolumina berechnet. Dann wurde der klinische THS-Effekt mit Werten dieser Verbindungskarten korreliert und für beide Kohorten ein Netzwerk errechnet, welches den optimalen therapeutischem Nutzen abbildete. Im direkten Vergleich waren diese zwei Netzwerke in so hohem Maße kongruent, dass der tatsächliche THS-Effekt einer einzelnen Stimulation durch die Ähnlichkeit des Konnektivitätsmusters zu der jeweils anderen Kohorte zu beschreiben war (R= 0.37, p< 0.001; R= 0.34, p= 0.032). In einer zweiten Analyse wurden ausschließlich kongruent überlagerte Werte der GPi-Netzwerkkarte und STN-Netzwerkkarte zu einer zielstrukturunabhängigen Karte verbunden. Diese Karte, die somit ein gemeinsames neuronales Netzwerk der beiden unterschiedlichen Zielstrukturen abbildete, wurde erneut mit den einzelnen Verbindungskarten der jeweiligen Kohorte korreliert. Diese nun von einzelnen Zielorten losgelöste Netzwerkkarte beschrieb die Varianz der Daten robuster als beide zielortabhängigen Netzwerkkarten. Diese Ergebnisse unterstützen die Annahme eines gemeinsamen funktionellen Netzwerks bei optimaler THS im IPS, unabhängig vom genauen anatomischen Stimulationsort. Die vorliegende Arbeit stellt unseres Wissens die erste Beschreibung eines zielortunabhängigen funktionellen Netzwerks dar, dessen Kenntnis zum Verständnis und für weitere Untersuchungen von THS sowie für nichtinvasive Neuromodulation von Nutzen ist.Deep brain stimulation (THS) is an established procedure for advanced idiopathic Parkinson's disease (IPS) patients to control dopamine induced dyskinesias and symptom fluctuations. Anatomical targets for surgical implantation of electrodes are the subthalamic nucleus (STN) and globus pallidus internus (GPi). However, equal effectiveness in these two nuclei has not been conclusively discussed, a categorically superior target lacks despite numerous studies. This study retrospectively compares effective THS in two cohorts of 94 patients with STN and 28 patients with GPi stimulation using connectivity analyses. The hypothesis was the existence of a common functional network modulated by THS of different areas. By merging pre- and postoperative imaging, the localization of each electrode was first reconstructed and corresponding areas were identified using a functional connectome to generate individual maps, thus containing the functional network fingerprints of each stimulation. In a next step, the therapeutic THS effect was correlated voxel-wise with values of the network maps, generating maps for both cohorts, each representing the network associated with an optimal therapeutic outcome of the patients upon stimulation. When contrasted, the two networks resembled each other to such an extent that the actual THS effect of a single stimulation could be described using the other cohort (R= 0.37, p< 0.001; R= 0.34, p= 0.032). In a second analysis, exclusively congruent overlaid values of the GPi network and STN network maps were fused into one map. This map, representing a common identified brain network of the two different target structures was now compared with the individual network maps of each cohort. Crucially, correlations of individual stimuli to the optimal connectivity from a common STN and GPi network were shown to be more robust than to their own cohort map alone. These results support the assumption of a shared functional network at optimal THS in the IPS, independent of stimulation location. Present work represents the first description of a target independent functional network in IPS. The description of this network could contribute to the fundamental understanding of the effects of THS and provide new impulses for noninvasive applications including transcranial magnetic stimulation or transcranial direct current stimulation

Phase-based regional oxygen metabolism (PROM) using MRI

Venous oxygen saturation (Yv) in cerebral veins and the cerebral metabolic rate of oxygen (CMRO2) are important indicators for brain function and disease. Although MRI has been used for global measurements of these parameters, currently there is no recognized technique to quantify regional Yv and CMRO2 using noninvasive imaging. This article proposes a technique to quantify CMRO2 from independent MRI estimates of Yv and cerebral blood flow. The approach uses standard gradient-echo and arterial spin labeling acquisitions to make these measurements. Using MR susceptometry on gradient-echo phase images, Yv was quantified for candidate vein segments in gray matter that approximate a long cylinder parallel to the main magnetic field. Local cerebral blood flow for the identified vessel was determined from a corresponding region in the arterial spin labeling perfusion map. Fick's principle of arteriovenous difference was then used to quantify CMRO2 locally around each vessel. Application of this method in young, healthy subjects provided gray matter averages of 59.6% ± 2.3% for Yv, 51.7 ± 6.4 mL/100 g/min for cerebral blood flow, and 158 ± 18 μmol/100 g/min for CMRO2 (mean ± SD, n = 12), which is consistent with values previously reported by positron emission tomography and MRI. Magn Reson Med, 2012.National Institutes of Health (U.S.) (NIH grant T90-DA022759)National Institutes of Health (U.S.) (NIH grant T32-GM07753)Siemens Aktiengesellschaft (Siemens-MIT Alliance)National Institutes of Health (U.S.) (NIH grant R01- EB007942

Accuracy of the Spot Sign on Computed Tomography Angiography as a Predictor of Haematoma Enlargement after Acute Spontaneous Intracerebral Haemorrhage: A Systematic Review

Background: A common early complication of intracerebral haemorrhage (ICH) is haematoma enlargement (HE), a strong independent predictor of a poor outcome. Therapeutic options to limit haematoma progression are currently scarce. Haemostatic therapy may be effective in patients with ICH, but it carries the risk of thromboembolic events in unselected patients. Accurate patient selection would, therefore, be of key importance for delivering potentially successful therapeutic strategies. Currently, there is no gold standard to accurately predict HE. The presence of contrast extravasation within the haematoma on computed tomography angiography (CTA), the 'spot sign', has been reported in several studies and seems a particularly promising marker but lacks a standardised evaluation so far. Summary: We conducted a systematic review of published data to address the research question: In adults with acute spontaneous ICH, how accurately does the spot sign predict HE on follow-up imaging and thus poor functional outcome or mortality? We searched PubMed and Embase databases (from 1980 to May 2012), using a highly sensitive search strategy and including all studies involving adult patients with spontaneous ICH evaluated with CTA and follow-up CT scans, reporting any measure of clinical outcome, and reporting or allowing calculation of accuracy measures of the spot sign in predicting HE and clinical outcome. Baseline characteristics, accuracy measures and effect measures, as well as bias assessment, were reported according to PRISMA recommendations. The quality of the studies was appraised using an adapted version of the REMARK reporting recommendations. From 259 potentially relevant studies, we finally selected 6 studies (1 of them was a multicentre cohort study) covering a total of 709 patients. Studies varied substantially in terms of size, methodological quality, definitions of terms, outcomes selected and results. In particular, definition of the spot sign was not consistent in all studies. Furthermore, the only outcome measure consistently available was HE, while definitions and analyses of clinical outcomes seemed not adequate. Lastly, the choice of candidate variables for univariate and multivariate analyses did not include all determinants of HE and poor functional outcome. High heterogeneity was demonstrated (I2: 94% for HE) with substantial potential of bias. Key Messages: Studies of the spot sign are diverse and therefore complex to interpret. Our research question could not be answered due to heterogeneity and potential of bias in the selected studies. Further appropriately powered studies using standardised definitions and taking all predictors of HE and poor clinical outcome into account are required for a proper clinical implementation

Social Avoidance in Depression:A Study Using a Social Decision-Making Task

Depression significantly affects interpersonal functioning. Social avoidance may play an important role in depression, limiting opportunities and social skills acquisition, contributing to the maintenance of social difficulties. In the last few years, the need for studying social interactions using interactive tasks has been highlighted. This study investigated social avoidance in unmedicated depressed (n = 26) and matched healthy control (n = 26) participants, using a novel computerized social decision-making task (the TEAM task). In this task, participants choose between a social option (playing in a team with a coplayer) and an individual option (playing alone). Although the social option is more profitable from a material point of view, it can also be challenging because of social comparison and guilt feelings for failing the team. It was found that the higher the rank of the coplayer, the stronger the negative emotions (shame, guilt) reported by participants and the more they opted for the individual option. Depressed participants reported significantly less positive (happiness) and more negative (shame, guilt, disappointment) feelings regarding the task. Importantly, depressed participants chose the individual option significantly more often than controls, which led to lower gains in this group. Furthermore, as the task progressed, controls selected the individual option less often, whereas depressed participants selected the individual option more often. Our findings illustrate the importance of social avoidance in depression and how this behavior can lead to negative consequences. They also highlight the role of social comparison and guilt-related processes in underlying social avoidance in depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved

HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma

<div><p>Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.</p></div