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The role of prediction error in linguistic generalization and item learning: evidence from an online eye-tracking study
No full textThe discriminative learning framework, grounded in principles of learning theory, was recently revitalized as a specific mechanism to carry out language acquisition within a domain-general, input-driven constructivist account. It specifies that language learning, rather than being guided by an innate linguistic system like Universal Grammar, could be constrained by obtaining negative evidence using prediction errors. Previous studies have tried to indirectly show the effect of prediction making on word-referent mapping by comparing the learning performance of two groups of learners who experienced language input with different input order conditions, where only one condition allowed cue competition. The current study applied eye tracking to the learning process and demonstrated direct evidence for the predictive behaviors during discriminative learning. Two learning experiments with a learning phase where cues predicted visual linguistic outcomes (labels) were conducted. Experiment 1 was a replication of an earlier word learning study – with eye tracking added – and showed that participants made predictive saccades towards positions of labels before they appeared for both high and low frequency conditions. Experiment 2 used a new cross-situational learning paradigm and did not demonstrate default fixations. Offline results showed weaker learning than previous studies and did not show above-chance accuracy for the low frequency trials. However, plot analysis of the individual variation for low frequency trials suggested that participants who failed to learn low frequency cues could have been persistently overgeneralizing in training. This overgeneralization pattern is discussed in the context of adult L2 learning
Unlocking the secrets of the regenerating fish heart: comparing regenerative models to shed light on successful regeneration
No full textThe adult human heart cannot repair itself after injury and, instead, forms a permanent fibrotic scar that impairs cardiac function and can lead to incurable heart failure. The zebrafish, amongst other organisms, has been extensively studied for its innate capacity to repair its heart after injury. Understanding the signals that govern successful regeneration in models such as the zebrafish will lead to the development of effective therapies that can stimulate endogenous repair in humans. To date, many studies have investigated cardiac regeneration using a reverse genetics candidate gene approach. However, this approach is limited in its ability to unbiasedly identify novel genes and signalling pathways that are essential to successful regeneration. In contrast, drawing comparisons between different models of regeneration enables unbiased screens to be performed, identifying signals that have not previously been linked to regeneration. Here, we will review in detail what has been learnt from the comparative approach, highlighting the techniques used and how these studies have influenced the field. We will also discuss what further comparisons would enhance our knowledge of successful regeneration and scarring. Finally, we focus on the Astyanax mexicanus, an intraspecies comparative fish model that holds great promise for revealing the secrets of the regenerating heart
MS Greaves 16: Saʿdī, Gulistān
No full textSelections photographed by Dr. Julia Bray for the project "Arabic Books and Astronomy in 17th C Oxford
The politics of the second vaccine: debates surrounding ebola vaccine trials in the Eastern Democratic Republic of the Congo
No full textTwo experimental Ebola vaccines were deployed during the tenth Ebola epidemic (2018–20) in the Democratic Republic of the Congo (DRC). The first, the Ervebo vaccine manufactured by Merck, was used as part of a ring vaccination in the epicentre of the epidemic in North Kivu. In 2019, the prime- (Ad26.ZEBOV) and boost- (MVA-BN-Filo) vaccine manufactured by Johnson & Johnson (J&J) became the second vaccine against Ebola, deployed by the DRC-EB-001 vaccine trial in Goma, North Kivu. There was international debate as to the value and ethics of testing a second vaccine in an epidemic context. This article examines how this debate unfolded among actual and potential DRC-EB-001 trial participants in Goma. Drawing on ethnographic observation, interviews and focus groups, it explores how the trial was perceived and contested on the ground and situated in broader debates about the ethics of clinical trials, especially during the COVID-19 pandemic. We illustrate how debates around the ethics of clinical research are not simply centred on bioethical principles but are inseparable from local political dynamics and broader contests about governance, inequality and exclusion
Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex
No full textPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders
Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial
No full textBACKGROUND: The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks' gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic.
METHODS: This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0-28+ 6 weeks' gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0-28+ 6 weeks' gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks' postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age.
DISCUSSION: Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done. Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks' postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age.
TRIAL REGISTRATION: ISRCTN84264977 . Date assigned: 15/09/2010
Class-agnostic segmentation loss and its application to salient object detection and segmentation
No full textIn this paper we present a novel loss function, called class-agnostic segmentation (CAS) loss. With CAS loss the class descriptors are learned during training of the network. We don’t require to define the label of a class a-priori, rather the CAS loss clusters regions with similar appearance together in a weakly-supervised manner. Furthermore, we show that the CAS loss function is sparse, bounded, and robust to class-imbalance. We first apply our CAS loss function with fully-convolutional ResNet101 and DeepLab-v3 architectures to the binary segmentation problem of salient object detection. We investigate the performance against the state-of-the-art methods in two settings of low and high-fidelity training data on seven salient object detection datasets. For low-fidelity training data (incorrect class label) class-agnostic segmentation loss outperforms the state-of-the-art methods on salient object detection datasets by staggering margins of around 50%. For high-fidelity training data (correct class labels) class-agnostic segmentation models perform as good as the state-of-the-art approaches while beating the state-of-the-art methods on most datasets. In order to show the utility of the loss function across different domains we then also test on general segmentation dataset, where class-agnostic segmentation loss outperforms competing losses by huge margins
Prevalence, risk and protective indicators of common mental disorders among young people living with HIV compared to their uninfected peers from the Kenyan coast: a cross-sectional study
No full textBACKGROUND: In sub-Saharan Africa, common mental disorders (CMDs) like depression and anxiety are under-investigated amongst young people living with HIV (YLWH). To address the gap, in Kenya we: a) determined the prevalence of CMDs among YLWH compared to their uninfected peers; b) investigated HIV status as an independent predictor of CMDs in young people; c) investigated CMDs risk and protective indicators with more focus on YLWH.
METHODS: Between November 2018 and September 2019, 819 young people aged 18-24 years (407 HIV-infected) were recruited from two Counties on the Kenyan coast. Locally adapted pre-existing mental health measures, Patient Health Questionnaire (9-item) and Generalized Anxiety Disorder scale (7-item), were administered among other questionnaires via audio computer-assisted self-interview. Logistic regression was used to determine the correlates of CMDs.
RESULTS: Prevalence of CMDs was significantly elevated among YLWH compared to their uninfected peers i.e. 29% vs. 12%; p < 0.001 for depressive symptoms, 19% vs. 8%; p < 0.001 for anxiety symptoms, and 16% vs. 5%; p < 0.001 for comorbid depressive and anxiety symptoms. HIV status independently predicted depressive symptoms and its co-occurrence with anxiety symptoms. Among YLWH, negative life events, higher perceived HIV-related stigma and low adherence to antiretroviral therapy were the risk indicators for elevated CMDs. Among HIV-uninfected youths, death of both parents was a risk indicator for elevated depressive symptoms. Protective indicators against CMDs among youths with and without HIV included higher social support and health-related quality of life.
CONCLUSION: At the Kenyan coast, YLWH have significantly higher burden of CMDs compared to their uninfected peers. Being HIV-positive as a youth in this setting is predictive of more depressive symptoms and its comorbidity with anxiety symptoms. YLWH at high risk of CMDs in coastal Kenya can benefit from early detection, referral and treatment if routine screening for CMDs is integrated in their care package. The mental wellbeing of bereaving HIV-unaffected youths could be improved through continued support to help them come to terms with their loss. At the community level, programmes strengthening the social capital or improving the overall quality of life of youths with or without HIV may be beneficial to their mental health
Measurement properties of radiographic outcome measures in Psoriatic Arthritis: A systematic review from the GRAPPA-OMERACT initiative
No full textBackground
Structural damage is as an important outcome in the Psoriatic Arthritis (PsA) Core Domain Set and its assessment is recommended at least once in the development of a new drug.
Objectives
To conduct a systematic review (SR) to identify studies addressing the measurement properties of radiographic outcome instruments for structural damage in PsA and appraise the evidence through the Outcome Measures in Rheumatology (OMERACT) Filter 2.1 Framework Instrument Selection Algorithm (OFISA).
Methods
A SR was conducted using search strategies in EMBASE and MEDLINE to identify full-text English studies which aimed to develop or assess the measurement properties of radiographic outcome instruments in PsA. Determination of eligibility and data extraction was performed independently by two reviewers with input from a third to achieve consensus. Two reviewers assessed the methodology and results of eligible studies and synthesized the evidence using OMERACT methodology.
Results
Twelve articles evaluating radiographic instruments were included. The articles assessed nine peripheral (hands, wrists and/or feet) and six axial (spinal and/or sacroiliac joints) radiographic instruments. The peripheral radiographic instruments with some evidence for reliability, cross-sectional construct validity and longitudinal construct validity were the Ratingen and modified Sharp van der Heijde scores. No instruments had evidence for clinical trial discrimination or thresholds of meaning. There was limited evidence for the measurement properties of all identified axial instruments.
Conclusion
There are significant knowledge gaps in the responsiveness of peripheral radiographic instruments. Axial radiographic instruments require further validation, and the need to generate novel instruments and utilise other imaging modalities should be considered
Neutralizing monoclonal antibodies for treatment of COVID-19
No full textSeveral neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants