Search bioRxivSearch

SEARCH · Search bioRxiv

Results for “Clinical Trials”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

350 records · Page 20Linked to original sources

Revealing neuro-computational mechanisms of reinforcement learning and decision-making with the hBayesDM package

Reinforcement learning and decision-making (RLDM) provide a quantitative framework and computational theories, with which we can disentangle psychiatric conditions into basic dimensions of neurocognitive functioning. RLDM offer a novel approach to assess and potentially diagnose psychiatric patients, and there is growing enthusiasm on RLDM and Computational Psychiatry among clinical researchers. Such a framework can also provide insights into the brain substrates of particular RLDM processes as exemplified by model-based functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG). However, many researchers often find the approach too technical and have difficulty adopting it for their research. Thus, there remains a critical need to develop a user-friendly tool for the wide dissemination of computational psychiatric methods. We introduce an R package called hBayesDM (hierarchical Bayesian modeling of Decision-Making tasks), which offers computational modeling on an array of RLDM tasks and social exchange games. The hBayesDM package offers state-of-the-art hierarchical Bayesian modeling, where both individual and group parameters (i.e., posterior distributions) are estimated simultaneously in a mutually constraining fashion. At the same time, it is extremely user-friendly: users can perform computational modeling, output visualization, and Bayesian model comparisons-each with a single line of coding. Users can also extract trial-by-trial latent variables (e.g., prediction errors) required for model-based fMRI/EEG. With the hBayesDM package, we anticipate that anyone with minimal knowledge of programming can take advantage of cutting-edge computational modeling approaches and investigate the underlying processes of and interactions between multiple decision-making (e.g., goal-directed, habitual, and Pavlovian) systems. In this way, it is our expectation that the hBayesDM package will contribute to the dissemination of advanced modeling approaches and enable a wide range of researchers to easily perform computational psychiatric research within their populations.

Neuroscience

Transcranial direct current stimulation over left inferior frontal cortex improves speech fluency in adults who stutter

Stuttering is a neurodevelopmental disorder affecting 5% of children, and persisting in 1% of adults. Promoting lasting fluency improvement in adults who stutter is a particular challenge. Novel interventions to improve outcomes are required, therefore. Previous work in patients with acquired motor and language disorders reported enhanced benefits of behavioural therapies when paired with transcranial direct current stimulation (tDCS). Here, we report the results of the first trial investigating whether tDCS can improve speech fluency in adults who stutter. Thirty adult men who stutter completed a randomized, double-blind, controlled trial of anodal tDCS over left inferior frontal cortex. Fifteen men received 20 minutes of 1-mA tDCS on five consecutive days while speech fluency was temporarily induced using choral and metronome-timed speech. The other 15 men received the same speech fluency intervention with sham stimulation. We predicted that applying anodal tDCS to the left inferior frontal cortex during speech production with temporary fluency inducers would result in longer-lasting fluency improvements. Speech fluency during reading and conversation was assessed at baseline, before and after the stimulation on each day of the five-day intervention, and at 1 and 6 weeks after the end of the intervention. TDCS combined with speech fluency training significantly reduced the percentage of disfluent speech measured 1 week after the intervention compared with fluency intervention alone. At 6 weeks after the intervention, this improvement was maintained during reading but not during conversation. Outcome scores at both post-intervention time points on a clinical assessment tool (the Stuttering Severity Instrument - version 4) also showed significant improvement in the group receiving tDCS compared with the sham group, in whom fluency was unchanged from baseline. We conclude that tDCS combined with behavioural fluency intervention has the capacity to improve fluency in adults who stutter. tDCS thereby offers a potentially useful adjunct to future speech therapy interventions for this population, for whom therapy outcomes are currently limited.

neuroscience

Offline coil position denoising enhances detection of TMS effects

OBJECTIVETranscranial magnetic stimulation (TMS) is extensively used in basic and clinical neuroscience. Previous work has shown substantial residual variability in TMS effects even despite use of on-line visual feedback monitoring of coil position. Here, we aimed to evaluate if off-line denoising of variability induced by neuronavigated coil position and orientation deviations can enhance detection of TMS effects.\n\nMETHODSRetrospective modeling was used to denoise the impact of common neuronavigated coil position and rotation deviations during TMS experimental sessions on motor evoked potentials (MEP) to single pulse TMS.\n\nRESULTSNeuronavigated coil deviations explained approximately 44% of total MEP amplitude variability. Offline denoising led to a 136.71% improvement in the signal to noise ratio (SNR) of corticospinal excitability measurements. CONCLUSIONS: Offline modeling enhanced detection of TMS effects by removing variability introduced by neuronavigated coil deviations.\n\nSIGNIFICANCEThis approach could allow more accurate determination of TMS effects in cognitive and interventional neuroscience.\n\nHIGHLIGHTSO_LICoil deviations impact TMS effects despite use of on-line neuronavigation feedback.\nC_LIO_LIOffline denoising of coil deviation impacts on TMS effects significantly reduced variability at trial level.\nC_LIO_LIOffline denoising also significantly improved overall SNR of TMS effects.\nC_LI

neuroscience

Genetic networks of the oxytocin system in the human brain: A gene expression and large-scale fMRI meta-analysis study

Oxytocin is a neuropeptide involved in animal and human reproductive and social behaviour, with potential implications for a range of psychiatric disorders. However, the therapeutic potential of oxytocin in mental health care suggested by animal research has not been successfully translated into clinical practice, partly due to a poor understanding of the expression and distribution of the oxytocin signaling pathway in the human brain, and its complex interactions with other biological systems. Among the genes involved in the oxytocin signaling pathway, three genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (central oxytocin secretion). We characterized the distribution of the OXT, OXTR, and CD38 mRNA across the brain, identified putative gene pathway interactions by comparing gene expression patterns across 29131 genes, and assessed associations between gene expression patterns and cognitive states via large-scale fMRI meta-analysis. In line with the animal literature, oxytocin pathway gene expression was enriched in central, temporal, and olfactory regions. Across the brain, there was high co-expression of the oxytocin pathway genes with both dopaminergic (DRD2) and muscarinic acetylcholine (CHRM4) genes, reflecting an anatomical basis for critical gene pathway interactions. Finally, fMRI meta-analysis revealed that oxytocin pathway maps correspond with motivation and emotion processing, demonstrating the value of probing gene expression maps to identify brain functional targets for future pharmacological trials.

neuroscience

A mechanistic basis for CD8+ T cell expansion sensitivity as a predictor of HIV post-treatment control

A key goal in HIV-1 cure research is to understand why some individuals control viral rebound after stopping antiretroviral therapy (ART). Recent human studies have identified responding CD8+ T cells expressing Ki-67 and the transcription factor TCF-1 as correlates of post-treatment control, but the mechanistic basis of this association remains unclear. Using the theoretical framework of Conway and Perelson, we fit mechanistic within-host models to viral load and CD8+ T cell data from 9 individuals in a combination immunotherapy trial following ART interruption. Although Ki-67 and TCF-1 measurements were not used for fitting, the inferred effector cell expansion sensitivity, i.e., the responsiveness of effector expansion to low antigen levels, shows a strong linear relationship with Ki-67 and TCF-1 levels at rebound (Pearsons r {approx} 0.8). Building on this, we show analytically that the post-rebound viral load set point is inversely proportional to the effector cell expansion sensitivity, and thus strongly correlates with cycling (Ki-67+) CD8+ T cells (r {approx} -0.8) at rebound, and a subset that expresses TCF-1 (r {approx} -0.9). In effect, individuals with a larger proportion of CD8+ T cells responding to viral rebound, and a greater representation of TCF-1 expressing cells within the responding subset, achieve markedly lower viral set points through a higher effector cell expansion sensitivity. This mechanism is consistent with prior modeling in a non-intervention ATI setting, suggesting it may generalize across more rebound contexts. Our results provide a mechanistic explanation why both Ki-67+ responding CD8+ T cells and their TCF-1-expressing subset predict post-treatment control, linking clinical correlation to its underlying cause and highlighting Ki-67 and TCF-1 as potential early biomarkers of HIV immunotherapy success.

immunology

The Influence of PTH 1-34 on the Osteogenic Characteristics of Adipose and Bone Marrow Derived Stem Cells from Juvenile and Ovarectomized Rats

Background: Mesenchymal Stem Cells (MSCs) are of growing interest in terms of bone regeneration; the majority of preclinical trials utilise bone marrow derived stem cells (bMSCs), though this is not without isolation and expansion difficulties\n\nObjective: We compare the characteristics of bone marrow and adipose derived cells from juvenile, adult and ovarectomized rats; also assessing the effect of hPTH 1-34, on their osteogenic potential.\n\nMethods: cells were isolated from the adipose and bone marrow of juvenile, adult and previously ovarectomized wistar rats. Cells were characterised with flowcytometery, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without co-culturing with 50nMol of intermittent PTH 1-34.\n\nResults: The juvenile and adult MSCs demonstrated significantly increased differentiation into bone and fat and superior migration towards SDF-1 than ovarectomized groups, this was the case for adipose and bone marrow derived cells equally. PTH increased parameters of osteogenic differentiation and migration to SDF-1, this was significant for all cell types, though had the most significant effect on cells derived from OVX animals. Bone marrow derived cells from all groups, showed increased mineralisation and migration to SDF-1 compared to adipose derived cells.\n\nConclusion: Juvenile MSCs showed significantly greater migration to SDF-1 and showed greater osteogenic and adipogenic differentiation compared to cells from osteopenic rats, this was true for bone marrow and adipose derived cells. The addition of PTH, increased the osteogenic characteristics and migration of all cells, and further illustrates the possible clinical utility of both PTH and MSCs from various sources in bone regenerative therapies

cell biology

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to-date, demonstrating approximately 50% efficacy in preventing HCMV acquisition in phase II trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and non-neutralizing anti-HCMV effector functions, and compared to an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and Domain I. Interestingly, vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this non-neutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound trimeric, membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, though were poor mediators of NK cell activation. Altogether, these data suggest that non-neutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.\n\nSignificanceThe CDC estimates that every hour, a child is born in the United States with permanent neurologic disability resulting from human cytomegalovirus (HCMV) infection - more than is caused by Down syndrome, fetal alcohol syndrome, and neural tube defects combined. A maternal vaccine to block transmission of HCMV to the developing fetus is a necessary intervention to prevent these adverse outcomes. The gB/MF59 vaccine is the most successful tested clinically to-date, achieving 50% reduction in HCMV acquisition. This manuscript establishes the function and epitope specificity of the humoral response stimulated by this vaccine that may explain the partial vaccine efficacy. Understanding the mechanism of gB/MF59-elicited protective immune responses will guide rational design and evaluation of the next generation of HCMV vaccines.

immunology

Meta-analysis and Commentary: Preemptive Correction of Arteriovenous Access Stenosis

BackgroundA recent meta-analysis by Ravani and colleagues (Ravani, P., et al., Am J Kidney Dis, 2016. 67(3): p. 446-60.) studied the effect of pre-emptive correction of arterio-venous dialysis vascular access versus deferred care, based on data from 11 trials. The authors reported a non-significant protective treatment effect of pre-emptive correction on access loss, while showing a significant protective effect on thrombosis rates conferred by pre-emptive correction. We revisit this analysis, including data extraction and effects of a heterogenous study population.\n\nMethodsWe repeated data extraction from all referenced publications in the meta-analysis by Ravani et al. and corrected event counts where applicable. We repeated the meta-analyses with access loss as the outcome for studies that recruited patients with arterio-venous fistulae (AVF) and grafts (AVG), respectively, using a random effects model with relative risk (RR) and risk difference (RD) of access loss as the outcomes of interest. We repeated data extraction from all referenced publications, and corrected event counts where applicable.\n\nResultsOur conclusions differ from the original findings in two ways. First, after some amendment of the event counts extracted from Mayer et al. (Vascular and Endovascular Surgery 1993), we find a significant overall positive effect of pre-emptive correction on arterio-venous access loss in the overall study population [RR 0.80 (95% CI 0.64 to 0.99), RD -0.07 (95% CI -0.12 to -0.02); Figure 1]. Secondly, we highlight the impact of heterogeneous study populations on the meta-analysis. Whereas the data do not conclusively show a benefit of pre-emptive correction for arteriovenous grafts (AVG; RR = 0.87, 95% CI: 0.69 - 1.11), they show a strong protective effect for arteriovenous fistulae (AVF; RR = 0.5, 95% CI: 0.29 to 0.86).\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC=\"FIGDIR/small/179580_fig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@af3c13org.highwire.dtl.DTLVardef@911a50org.highwire.dtl.DTLVardef@568cf1org.highwire.dtl.DTLVardef@3f3c08_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Meta-analysis of access loss, overall and by access type using risk ratio (RR) as the measure of association.\n\nC_FIG\n\nDiscussion and ConclusionThese findings corroborate clinical arguments such as superior long-term patency of AVF and the nature of AVG failure that often involve infectious causes. The available data indicate mild or no benefit of pre-emptive correction for AVG, but strongly support tight monitoring of dialysis accesses and preemptive intervention and correction upon the slightest suspicion of access stenosis for AVF.

epidemiology