Hippocampal and medial prefrontal cortices encode structural task representations following progressive and interleaved training schedules.

Memory generalisations may be underpinned by either encoding- or retrieval-based generalisation mechanisms and different training schedules may bias some learners to favour one of these mechanisms over the other. We used a transitive inference task to investigate whether generalisation is influenced by progressive vs randomly interleaved training, and overnight consolidation. On consecutive days, participants learnt pairwise discriminations from two transitive hierarchies before being tested during fMRI. Inference performance was consistently better following progressive training, and for pairs further apart in the transitive hierarchy. BOLD pattern similarity correlated with hierarchical distances in the left hippocampus (HIP) and medial prefrontal cortex (MPFC) following both training schedules. These results are consistent with the use of structural representations that directly encode hierarchical relationships between task features. However, such effects were only observed in the MPFC for recently learnt relationships. Furthermore, the MPFC appeared to maintain structural representations in participants who performed at chance on the inference task. We conclude that humans preferentially employ encoding-based mechanisms to store map-like relational codes that can be used for memory generalisation. These codes are expressed in the HIP and MPFC following both progressive and interleaved training but are not sufficient for accurate inference.

The Neural Representation of Events Is Dominated by Elements that Are Most Reliably Present.

An episodic memory is specific to an event that occurred at a particular time and place. However, the elements that constitute the event-the location, the people present, and their actions and goals-might be shared with numerous other similar events. Does the brain preferentially represent certain elements of a remembered event? If so, which elements dominate its neural representation: those that are shared across similar events, or the novel elements that define a specific event? We addressed these questions by using a novel experimental paradigm combined with fMRI. Multiple events were created involving conversations between two individuals using the format of a television chat show. Chat show "hosts" occurred repeatedly across multiple events, whereas the "guests" were unique to only one event. Before learning the conversations, participants were scanned while viewing images or names of the (famous) individuals to be used in the study to obtain person-specific activity patterns. After learning all the conversations over a week, participants were scanned for a second time while they recalled each event multiple times. We found that during recall, person-specific activity patterns within the posterior midline network were reinstated for the hosts of the shows but not the guests, and that reinstatement of the hosts was significantly stronger than the reinstatement of the guests. These findings demonstrate that it is the more generic, familiar, and predictable elements of an event that dominate its neural representation compared with the more idiosyncratic, event-defining, elements.

Activation of Person Knowledge in Medial Prefrontal Cortex during the Encoding of New Lifelike Events.

Our knowledge about people can help us predict how they will behave in particular situations and interpret their actions. In this study, we investigated the cognitive and neural effects of person knowledge on the encoding and retrieval of novel life-like events. Healthy human participants learnt about two characters over a week by watching 6 episodes of one of two situation comedies, which were both centered on a young couple. In the scanner, they watched and then silently recalled 20 new scenes from both shows that were all set in unfamiliar locations: 10 from their trained show and 10 from the untrained show. After scanning, participants' recognition memory was better for scenes from the trained show. The functional magnetic resonance imaging (fMRI) patterns of brain activity when watching the videos were reinstated during recall, but this effect was not modulated by training. However, person knowledge boosted the similarity in fMRI patterns of activity in the medial prefrontal cortex (MPFC) when watching the new events involving familiar characters. Our findings identify a role for the MPFC in the representation of schematic person knowledge during the encoding of novel, lifelike events.

A Pragmatic Study to Evaluate the Use of a Rapid Diagnostic Test to Detect Group A Streptococcal Pharyngitis in Children With the Aim of Reducing Antibiotic Use in a UK Emergency Department.

OBJECTIVE: Sore throat is a common presentation to the children's emergency department (ED), and many patients are likely prescribed antibiotics unnecessarily. We aimed to reduce antibiotic prescribing for sore throat in our UK ED through use of an established scoring system combined with a rapid diagnostic test (RDT) to detect group A streptococcal (GAS) pharyngitis. METHODS: AB single-subject and diagnostic accuracy studies were used to measure both antibiotic prescribing rates over time and the performance of the McIsaac clinical score combined with RDT to screen for and treat GAS pharyngitis. All children between the age of 6 months and 16 years with symptoms of sore throat were eligible for inclusion. The study adhered to SQUIRE guidelines. RESULTS: During 2014 and 2016, antibiotic prescribing rates for 210 children at baseline (median age, 3 years) and 395 children during the intervention (median age, 2 years) were assessed. The baseline prescribing rate was 79%, whereas rates after intervention were 24% and 27%, respectively. The RDT had an acceptable false-negative rate of 7.9%, poor sensitivity of 64.3%, and a negative predictive value of 92.1% when compared with conventional throat culture. A McIsaac score of 3 or more had good sensitivity (92.11%) but very low specificity (12.62%) for predicting GAS infection. CONCLUSIONS: Despite poor RDT sensitivity and the McIsaac score's poor specificity in children, their use in combination decreased antibiotic prescribing rates in a children's ED setting.

The brain regions supporting schema-related processing of people's identities.

Schematic knowledge about people helps us to understand their behaviour in novel situations. The ventromedial prefrontal cortex (vmPFC) and hippocampus play important, yet poorly understood, roles in schema-based processing. Here, we manipulated schematic knowledge by familiarizing participants over the course of a week to the two lead characters of one of two TV shows. Then during MRI scanning, they viewed pictures of all four characters and performed a recognition memory test afterwards. Memory was also tested for short videos. Schematic knowledge boosted performance on both memory tests. Whole-brain analyses revealed knowledge related activation increases in the vmPFC and retrosplenial cortex while a similar effect was identified in a hippocampal region-of-interest. Representational similarity analyses identified person-specific patterns of activity in the vmPFC but not hippocampus, but no effect of familiarization. Our findings suggest complementary roles for the vmPFC and hippocampus in processing schematic knowledge that was acquired in a naturalistic manner.

Paediatric contacts with the UK out-of-hours primary care service and contact outcomes: a regional service evaluation.

BACKGROUND: Demand on hospital emergency departments for paediatric problems is increasing. However, the volume and nature of paediatric health demands placed on other parts of the urgent care system have not been explored. This understanding is an important first step in developing and improving out-of-hospital care. We aimed to describe the volume, nature, and outcomes of paediatric contacts with out-of-hours general practice (OOH GP). We performed a retrospective service evaluation using data from 12 months of paediatric patient contacts with the Oxfordshire OOH GP service. METHODS: A database of contacts with the Oxfordshire OOH GP service was created for a 12 month period from December 2014 to November 2015. Descriptive statistics were calculated using SPSS Version 25. RESULTS: 27,455 contacts were made by 18,987 individuals during a 12 month period. The majority of these were for children aged under 5. Over 70% of contacts were at the weekend. The peak contact period was between 18:30 and 21:30. Over 40% of contacts resulted in advice only (no onward referral, requirement for GP follow up, or prescription). 19.7% of contacts resulted in an antibiotic prescription, most commonly those linked with ear, chest, and throat infections. DISCUSSION: Paediatric contacts with the Oxfordshire OOH GP service were predominantly in younger age groups and in the evening, with 19.7% resulting in an antibiotic prescription. Almost half of the contacts had no follow up or prescription, suggesting non-prescribing health care professionals could be involved in providing care in OOH GP. Further research should consider how children and their parents can be best supported to optimise OOH consulting.

Human hippocampal theta power indicates movement onset and distance travelled.

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a self-paced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movement-onset periods are associated with a significant increase in both low (2-5 Hz)- and high (6-9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation.

Not just little adults: preparing a children's emergency department for COVID-19.

COVID-19 presented unique challenges in preparing our stand-alone children's emergency department for the pandemic and has demonstrated well the paediatric adage, 'children aren't little adults'.

Predicting memory formation over multiple study episodes.

Repeated study typically improves episodic memory performance. Two different types of explanations of this phenomenon have been put forward: (1) reactivating the same representations strengthens and stabilizes memories, or (2) greater encoding variability benefits memory by promoting richer traces. The present experiment directly compared these predictions in a design with multiple repeated study episodes, allowing to dissociate memory for studied items and their context of study. Participants repeatedly encoded names of famous people four times, either in the same task, or in different tasks. During the test phase, an old/new judgment task was used to assess item memory, followed by a source memory judgment about the encoding task. Consistent with predictions from the encoding variability view, encoding stimulus in different contexts resulted in higher item memory. In contrast, consistent with the reactivation view, source memory performance was higher when participants encoded stimuli in the same task repeatedly. Taken together, our findings indicate that encoding variability benefits episodic memory, by increasing the number of items that are recalled. These benefits are however at the expenses of source recollection and memory for details, which are decreased, likely due to interference and generalization across contexts.

The processing of color preference in the brain.

Decades of research has established that humans have preferences for some colors (e.g., blue) and a dislike of others (e.g., dark chartreuse), with preference varying systematically with variation in hue (e.g., Hurlbert and Owen, 2015). Here, we used functional MRI to investigate why humans have likes and dislikes for simple patches of color, and to understand the neural basis of preference, aesthetics and value judgements more generally. We looked for correlations of a behavioural measure of color preference with the blood oxygen level-dependent (BOLD) response when participants performed an irrelevant orientation judgement task on colored squares. A whole brain analysis found a significant correlation between BOLD activity and color preference in the posterior midline cortex (PMC), centred on the precuneus but extending into the adjacent posterior cingulate and cuneus. These results demonstrate that brain activity is modulated by color preference, even when such preferences are irrelevant to the ongoing task the participants are engaged. They also suggest that color preferences automatically influence our processing of the visual world. Interestingly, the effect in the PMC overlaps with regions identified in neuroimaging studies of preference and value judgements of other types of stimuli. Therefore, our findings extends this literature to show that the PMC is related to automatic encoding of subjective value even for basic visual features such as color.

Multiscale Integration of Contextual Information During a Naturalistic Task.

Everyday experience requires rapid and automatic integration of incoming stimuli with previously stored knowledge. Prior knowledge can help to construct a general "situation model" of the event, as well as aid comprehension of an ongoing narrative. Using fMRI in healthy adult humans, we investigated processing of videos whose locations and characters were always familiar but whose narratives were either a continuation or noncontinuation of an earlier video (high context (HC) or low context (LC), respectively). Responses in parahippocampal gyrus and retrosplenial cortex were composed of an initial transient, locked to the video onsets, followed by a period of lower amplitude activation that was greater in the LC condition. This may reflect rapid processing of core components of situation models such as location and characters and more gradual incorporation of their narrative themes. By contrast, activity increases in left hemisphere middle temporal gyrus (MTG), angular gyrus, and inferior frontal gyrus were maintained throughout the videos and were higher for HC versus LC videos. Further, activity in the left MTG peaked earlier in the HC condition. We suggest that these regions support representations of the specific interlinked concepts necessary to comprehend an ongoing narrative, which are already established for the HC videos.

The role of the hippocampus in generalizing configural relationships.

The hippocampus has been implicated in integrating information across separate events in support of mnemonic generalizations. These generalizations may be underpinned by processes at both encoding (linking similar information across events) and retrieval ("on-the-fly" generalization). However, the relative contribution of the hippocampus to encoding- and retrieval-based generalizations is poorly understood. Using fMRI in humans, we investigated the hippocampal role in gradually learning a set of spatial discriminations and subsequently generalizing them in an acquired equivalence task. We found a highly significant correlation between individuals' performance on a generalization test and hippocampal activity during the test, providing evidence that hippocampal processes support on-the-fly generalizations at retrieval. Within the same hippocampal region there was also a correlation between activity during the final stage of learning (when all associations had been learnt but no generalization was required) and subsequent generalization performance. We suggest that the hippocampus spontaneously retrieves prior events that share overlapping features with the current event. This process may also support the creation of generalized representations during encoding. These findings are supportive of the view that the hippocampus contributes to both encoding- and retrieval-based generalization via the same basic mechanism; retrieval of similar events sharing common features. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Categorical encoding of color in the brain.

The areas of the brain that encode color categorically have not yet been reliably identified. Here, we used functional MRI adaptation to identify neuronal populations that represent color categories irrespective of metric differences in color. Two colors were successively presented within a block of trials. The two colors were either from the same or different categories (e.g., "blue 1 and blue 2" or "blue 1 and green 1"), and the size of the hue difference was varied. Participants performed a target detection task unrelated to the difference in color. In the middle frontal gyrus of both hemispheres and to a lesser extent, the cerebellum, blood-oxygen level-dependent response was greater for colors from different categories relative to colors from the same category. Importantly, activation in these regions was not modulated by the size of the hue difference, suggesting that neurons in these regions represent color categorically, regardless of metric color difference. Representational similarity analyses, which investigated the similarity of the pattern of activity across local groups of voxels, identified other regions of the brain (including the visual cortex), which responded to metric but not categorical color differences. Therefore, categorical and metric hue differences appear to be coded in qualitatively different ways and in different brain regions. These findings have implications for the long-standing debate on the origin and nature of color categories, and also further our understanding of how color is processed by the brain.

Consolidation of Complex Events via Reinstatement in Posterior Cingulate Cortex.

It is well-established that active rehearsal increases the efficacy of memory consolidation. It is also known that complex events are interpreted with reference to prior knowledge. However, comparatively little attention has been given to the neural underpinnings of these effects. In healthy adults humans, we investigated the impact of effortful, active rehearsal on memory for events by showing people several short video clips and then asking them to recall these clips, either aloud (Experiment 1) or silently while in an MRI scanner (Experiment 2). In both experiments, actively rehearsed clips were remembered in far greater detail than unrehearsed clips when tested a week later. In Experiment 1, highly similar descriptions of events were produced across retrieval trials, suggesting a degree of semanticization of the memories had taken place. In Experiment 2, spatial patterns of BOLD signal in medial temporal and posterior midline regions were correlated when encoding and rehearsing the same video. Moreover, the strength of this correlation in the posterior cingulate predicted the amount of information subsequently recalled. This is likely to reflect a strengthening of the representation of the video's content. We argue that these representations combine both new episodic information and stored semantic knowledge (or "schemas"). We therefore suggest that posterior midline structures aid consolidation by reinstating and strengthening the associations between episodic details and more generic schematic information. This leads to the creation of coherent memory representations of lifelike, complex events that are resistant to forgetting, but somewhat inflexible and semantic-like in nature.

The interference effect in arithmetic fact solving: An fMRI study.

Some multiplication facts share common digits with other, previously learned facts, and as a result, different problems are associated with different levels of interference. The detrimental effect of interference in arithmetic facts knowledge has been recently highlighted in behavioral studies, in children as well as in adults, both in typical and atypical development. The present study investigated the brain regions involved in the interference effect when solving multiplication problems. Twenty healthy adults carried out a multiplication task in an MRI scanner. The event-related design comprised problems whose interference level and problem size were manipulated in a 2×2 factorial design. After each trial, individuals were requested to indicate whether they solved the trial by retrieving the answer from long-term memory. This allowed us to examine which brain areas were sensitive to the interference effect and problem size effect as well as the retrieval strategy. The results highlighted two specific regions: the left angular gyrus was more activated for low interfering than for high interfering problems, and the right intraparietal sulcus was more activated for large problems than for small problems. In both regions, brain activity was not modulated by the other effect. These results suggest that the left angular gyrus is sensitive to the level of interference of the multiplication problems, whereas previously this region was thought to be more activated by small problems or by retrieval strategy. Here, in a design manipulating interference and problem size, while controlling for retrieval strategy, we showed that it rather reflects an automatic mapping between the problem and the answer stored in long-term memory. The right intraparietal sulcus was modulated by the problem size effect, which supports the idea that the problem size effect comes from the higher overlap between magnitude of the answers of large problems compared to small ones. Importantly, neither effects can be reduced to a strategy effect since they were present when analyzing only retrieval trials.

The effect of apolipoprotein E genotype on spatial processing in humans: A meta-analysis and systematic review.

The ε4 allele of the apolipoprotein E (APOE4) gene is an established risk factor for Alzheimer's disease but its impact on cognition in healthy adults across the lifespan is unclear. One cognitive domain that is affected early in the course of Alzheimer's disease is spatial cognition, yet the evidence for APOE-related changes in spatial cognition is mixed. In this meta-analysis we assessed the impact of carrying the APOE4 allele on five subdomains of spatial cognition across the lifespan. We included studies of healthy human participants where an APOE4-carrier group (heterozygous or homozygous) could be compared to a homozygous group of APOE3-carriers. We identified 156 studies in total from three databases (Pubmed, Scopus and Web of Science) as well as through searching cited literature and contacting authors for unpublished data. 122 studies involving 32,547 participants were included in a meta-analysis, and the remaining studies are included in a descriptive review. APOE4 carriers scored significantly lower than APOE3 carriers (θˆ = -.08 [-.14, -.02]) on tests of spatial long-term memory; this effect was very small and was not modulated by age. On other subdomains of spatial cognition (spatial construction, spatial working memory, spatial reasoning, navigation) there were no effects of genotype. Overall, our results demonstrate that the APOE4 allele exerts little influence on spatial cognitive abilities in healthy adults.

Clinician and parent views on urine collection in precontinent children in the UK: a qualitative interview study.

OBJECTIVE: To explore the experiences of healthcare professionals (HCPs) and parents of urine collection methods, to identify barriers to successful sampling and what could improve the process. DESIGN: Qualitative research, using individual semistructured interviews with HCPs and parents. The interviews were audiorecorded, transcribed and thematically analysed. SETTING: UK-based HCPs from primary and secondary care settings and parents with experience with urine collection in primary and/or secondary care settings. PARTICIPANTS: HCPs who were involved in aiding, supervising or ordering urine samples. Parents who had experience with urine collection in at least one precontinent child. RESULTS: 13 HCPs and 16 parents were interviewed. 2 participating HCPs were general practitioners (GPs), 11 worked in paediatric secondary care settings (8 were nurses and 3 were doctors). Two parents had children with underlying conditions where frequent urine collection was required to rule out infections.HCPs and parents reported that there were no straightforward methods of urine collection for precontinent children. Each method-'clean catch', urine bag and urine pad-had limitations and problems with usage. 'Clean catch', regarded as the gold standard by HCPs with a lower risk of contamination, often proved difficult for parents to achieve. Other methods had elevated risk of contamination but were more acceptable to parents because they were less challenging. Many of the parents expressed the need for more information about urine collection. CONCLUSIONS: Current methods of urine collection are challenging to use and may be prone to contamination. A new device is required to assist with urine collection in precontinent children, to simplify and reduce the stress of the situation for those involved. Parents are key partners in the process of urine collection with young children. Meeting their expressed need for more information could be an important way to achieve better-quality samples while awaiting a new device.

Infections diagnosed in children and young people screened for malaria in UK emergency departments: a retrospective multi-centre study.

BACKGROUND: Data on imported infections in children and young people (CYP) are sparse. AIMS: To describe imported infections in CYP arriving from malaria-endemic areas and presenting to UK emergency departments (ED) who were screened for malaria. METHODS: This is a retrospective, multi-centre, observational study nested in a diagnostic accuracy study for malaria rapid diagnostic tests. Any CYP < 16 years presenting to a participating ED with a history of fever and travel to a malaria-endemic area between 1 January 2016 and 31 December 2017 and who had a malaria screen as a part of standard care were included. Geographical risk was calculated for the most common tropical infections. RESULTS: Of the 1414 CYP screened for malaria, 44.0% (n = 622) arrived from South Asia and 33.3% (n = 471) from sub-Saharan Africa. Half (50.0%) had infections common in both tropical and non-tropical settings such as viral upper respiratory tract infection (URTI); 21.0% of infections were coded as tropical if gastro-enteritis is included, with a total of 4.2% (60) cases of malaria. CYP diagnosed with malaria were 7.44 times more likely to have arrived from sub-Saharan Africa than from South Asia (OR 7.44, 3.78-16.41). CONCLUSION: A fifth of CYP presenting to participating UK EDs with fever and a history of travel to a malaria-endemic area and who were screened for malaria had a tropical infection if diarrhoea is included. A third of CYP had no diagnosis. CYP arriving from sub-Saharan Africa had the greatest risk of malaria.Abbreviations: CYP: children and young people; ED: emergency department; PERUKI: Paediatric Emergency Research in the UK and Ireland; RDT: rapid diagnostic test; VFR: visiting friends and relatives.

The hippocampus and memory: insights from spatial processing.

The hippocampus appears to be crucial for long-term episodic memory, yet its precise role remains elusive. Electrophysiological studies in rodents offer a useful starting point for developing models of hippocampal processing in the spatial domain. Here we review one such model that points to an essential role for the hippocampus in the construction of mental images. We explain how this neural-level mechanistic account addresses some of the current controversies in the field, such as the role of the hippocampus in imagery and short-term memory, and discuss its broader implications for the neural bases of episodic memory.

Severity of the TGN1412 trial disaster cytokine storm correlated with IL-2 release.

AIM: To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs. METHODS: Cytokine ELISAs and a multi-array system were used to compare responses generated by different therapeutic mAbs using a solid phase assay. Flow cytometry was employed to determine the cellular source of those cytokines. RESULTS: Only TGN1412 and muromonab-CD3 stimulated CD4+ T-cell mediated cytokine release characterized by significant (all P < 0.0001) IFNγ, TNFα, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and IL-22 release, comparable with T-cell mitogen. Significantly greater (P < 0.0001) IL-2 release with TGN1412 (2894-6051 pg ml⁻¹) compared with muromonab-CD3 (62-262 pg ml⁻¹) differentiated otherwise comparable cytokine responses. Likewise, TGN1412 stimulated significantly more (P = 0.0001) IL-2 producing CD4+ T-cells than muromonab-CD3 and induced Th1, Th2, Th17 and Th22 subsets that co-release this cytokine. Significant TNFα release was observed with bevacizumab (P = 0.0001), trastuzumab (P = 0.0031) and alemtuzumab (P = 0.0177), but no significant IL-2 release. TGN1412 and muromonab-CD3 caused pro-inflammatory cytokine release despite significantly (both P < 0.0001) increasing numbers of T-cells with a regulatory phenotype. CONCLUSIONS: The severity of the adverse response to TGN1412 compared with muromonab-CD3 and other therapeutic mAbs correlates with the level of IL-2 release.