Virtual patients design and its effect on clinical reasoning and student experience : a protocol for a randomised factorial multi-centre study

Background Virtual Patients (VPs) are web-based representations of realistic clinical cases. They are proposed as being an optimal method for teaching clinical reasoning skills. International standards exist which define precisely what constitutes a VP. There are multiple design possibilities for VPs, however there is little formal evidence to support individual design features. The purpose of this trial is to explore the effect of two different potentially important design features on clinical reasoning skills and the student experience. These are the branching case pathways (present or absent) and structured clinical reasoning feedback (present or absent). Methods/Design This is a multi-centre randomised 2x2 factorial design study evaluating two independent variables of VP design, branching (present or absent), and structured clinical reasoning feedback (present or absent).The study will be carried out in medical student volunteers in one year group from three university medical schools in the United Kingdom, Warwick, Keele and Birmingham. There are four core musculoskeletal topics. Each case can be designed in four different ways, equating to 16 VPs required for the research. Students will be randomised to four groups, completing the four VP topics in the same order, but with each group exposed to a different VP design sequentially. All students will be exposed to the four designs. Primary outcomes are performance for each case design in a standardized fifteen item clinical reasoning assessment, integrated into each VP, which is identical for each topic. Additionally a 15-item self-reported evaluation is completed for each VP, based on a widely used EViP tool. Student patterns of use of the VPs will be recorded. In one centre, formative clinical and examination performance will be recorded, along with a self reported pre and post-intervention reasoning score, the DTI. Our power calculations indicate a sample size of 112 is required for both primary outcomes

Demonstration of all-or-none loss of imprinting in mRNA expression in single cells

Loss of imprinting (LOI) is the reactivation of the silenced allele of an imprinted gene, leading to perturbation of monoallelic expression. We tested the hypothesis that LOI of PLAGL1, a representative maternally imprinted gene, occurs through an all-or-none process leading to a mixture of fully imprinted and nonimprinted cells. Herein using a quantitative RT-PCR-based experimental approach, we measured LOI at the single cell level in human trophoblasts and demonstrated a broad distribution of LOI among cells exhibiting LOI, with the mean centered at ∼100% LOI. There was a significant (P < 0.01) increase in expression after 2 days of 5-aza-2′-deoxycytidine (AZA) treatment and a significant (P < 0.01) increase in LOI after both 1 and 2 days of AZA treatment, while the distribution remained broad and centered at ∼100% LOI. We propose a transcriptional pulsing model to show that the broadness of the distribution reflects the stochastic nature of expression between the two alleles in each cell. The mean of the distribution of LOI in the cells is consistent with our hypothesis that LOI occurs by an all-or-none process. All-or-none LOI could lead to a second distinct cell population that may have a selective advantage, leading to variation of LOI in normal tissues, such as the placenta, or in neoplastic cells

One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders

Autism spectrum disorders (ASDs), which include the prototypic autistic disorder (AD), Asperger’s syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental conditions of unknown aetiology. The current study investigated the metabolites in the methionine cycle, the transsulphuration pathway, folate, vitamin B 12 and the C677T polymorphism of the MTHFR gene in three groups of children diagnosed with AD ( n = 15), AS ( n = 5) and PDD-NOS ( n = 19) and their age- and sex-matched controls ( n = 25). No metabolic disturbances were seen in the AS patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine ( P = 0.01 and P = 0.03, respectively) and Α-aminobutyrate were observed ( P = 0.01 and P = 0.001, respectively). Only in the AD group, plasma cysteine ( P = 0.02) and total blood glutathione ( P = 0.02) were found to be reduced. Although there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine in AD patients, the plasma levels of these metabolites as well as the levels of homocysteine and cystathionine were not statistically different in any of the ASDs groups. The serum levels of vitamin B 12 and folate were in the normal range. The results of the MTHFR gene analysis showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the 677T allele was slightly more prevalent in AD patients. Our study indicates a possible role for the alterations in one carbon metabolism in the pathophysiology of ASDs and provides, for the first time, preliminary evidence for metabolic and genetic differences between clinical subtypes of ASDs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73924/1/j.1582-4934.2008.00463.x.pd

Losing ourselves:Active inference, depersonalization, and meditation

This is the final version. Available on open access from Frontiers Media via the DOI in this recordDisruptions in the ordinary sense of selfhood underpin both pathological and “enlightened” states of consciousness. People suffering from depersonalization can experience the loss of a sense of self as devastating, often accompanied by intense feelings of alienation, fear, and hopelessness. However, for meditative contemplatives from various traditions, “selfless” experiences are highly sought after, being associated with enduring peace and joy. Little is understood about how these contrasting dysphoric and euphoric experiences should be conceptualized. In this paper, we propose a unified account of these selfless experiences within the active inference framework. Building on our recent active inference research, we propose an account of the experiences of selfhood as emerging from a temporally deep generative model. We go on to develop a view of the self as playing a central role in structuring ordinary experience by “tuning” agents to the counterfactually rich possibilities for action. Finally, we explore how depersonalization may result from an inferred loss of allostatic control and contrast this phenomenology with selfless experiences reported by meditation practitioners. We will show how, by beginning with a conception of self-modeling within an active inference framework, we have available to us a new way of conceptualizing the striking experiential similarities and important differences between these selfless experiences within a unifying theoretical framework. We will explore the implications for understanding and treating dissociative disorders, as well as elucidate both the therapeutic potential, and possible dangers, of meditation.European Union Horizon 202

Table S2: fTCD categories for language lateralisation by group and sex

Background It has been suggested that failure to establish cerebral lateralisation may be related to developmental language disorder (DLD). There has been weak support for any link with handedness, but more consistent reports of associations with functional brain lateralisation for language. The consistency of lateralisation across different functions may also be important. We aimed to replicate previous findings of an association between DLD and reduced laterality on a quantitative measure of hand preference (reaching across the midline) and on language laterality assessed using functional transcranial Doppler ultrasound (fTCD). Methods From a sample of twin children aged from 6;0 to 11;11 years, we identified 107 cases of DLD and 156 typically-developing comparison cases for whom we had useable data from fTCD yielding a laterality index (LI) for language function during an animation description task. Handedness data were also available for these children. Results Indices of handedness and language laterality for this twin sample were similar to those previously reported for single-born children. There were no differences between the DLD and TD groups on measures of handedness or language lateralisation, or on a categorical measure of consistency of left hemisphere dominance. Contrary to prediction, there was a greater incidence of right lateralisation for language in the TD group (19.90%) than the DLD group (9.30%), confirming that atypical laterality is not inconsistent with typical language development. We also failed to replicate associations between language laterality and language test scores. Discussion and Conclusions Given the large sample studied here and the range of measures, we suggest that previous reports of atypical manual or language lateralisation in DLD may have been false positives

Keratan sulfate, a complex glycosaminoglycan with unique functional capability

From an evolutionary perspective keratan sulfate (KS) is the newest glycosaminoglycan (GAG) but the least understood. KS is a sophisticated molecule with a diverse structure, and unique functional roles continue to be uncovered for this GAG. The cornea is the richest tissue source of KS in the human body but the central and peripheral nervous systems also contain significant levels of KS and a diverse range of KS-proteoglycans with essential functional roles. KS also displays important cell regulatory properties in epithelial and mesenchymal tissues and in bone and in tumor development of diagnostic and prognostic utility. Corneal KS-I displays variable degrees of sulfation along the KS chain ranging from non-sulfated polylactosamine, mono-sulfated and disulfated disaccharide regions. Skeletal KS-II is almost completely sulfated consisting of disulfated disaccharides interrupted by occasional mono-sulfated N-acetyllactosamine residues. KS-III also contains highly sulfated KS disaccharides but differs from KS-I and KS-II through 2-O-mannose linkage to serine or threonine core protein residues on proteoglycans such as phosphacan and abakan in brain tissue. Historically, the major emphasis on the biology of KS has focused on its sulfated regions for good reason. The sulfation motifs on KS convey important molecular recognition information and direct cell behavior through a number of interactive proteins. Emerging evidence also suggest functional roles for the poly-N-acetyllactosamine regions of KS requiring further investigation. Thus further research is warranted to better understand the complexities of KS

Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Objective: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.  Methods: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.  Results: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.  Conclusion: Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months

Optical characterisation of long wavelength self-assembled quantum dot lasers

A detailed optical characterisation of (1.3 )InAs quantum-dot-in-well (DWELL) laser structures, is described

On the hierarchical inheritance of aftereffects in the visual system

The emotion perceived in a face can be influenced by prior exposure to a face expressing a different emotion. Here we show that displacement along a particular emotional axis, that encoding happiness and sadness, can be effected solely by a systematic change in the angle, at the centre of the mouth, between the left and right halves of the mouth. We then demonstrate that adaptation to a face with the mouth distorted to change this angle, such that the face expresses an emotion on this axis, causes a face with a neutral expression to be perceived as having the opposite expression. By abstracting the mouths from the faces and examining the magnitude of the angle aftereffects in the mouths alone and in an unfamiliar orientation, we show that the magnitudes of the angle aftereffects are sufficient to account for the changes in perceived emotion in the faces. Further, by applying the distortion to the mouths asymmetrically so that the distortion is manifested by a change in orientation of the mouth stimulus rather than a change in angle, we show that the magnitude of the aftereffect can be predicted by the local tilt aftereffect. We argue, therefore, that the aftereffects of emotion are due to misperception of morphology of the face and that the misperception is due to the local change in perceived orientation due to the systematic application of the tilt aftereffect in a tilt aftereffect field. All adaptation experiments were performed using stimuli that were either high-pass or low-pass filtered for spatial frequency. Results showed that the spatial frequency specificity of the aftereffects was the same for the face, angled mouth and oriented mouth stimuli, lending further support to the hypothesis that the aftereffects are instantiated in processes early in the visual cortex and that the aftereffects assumed to be higher level are, in fact, inherited