Case-based discussion: neonates on extracorporeal membrane oxygenation for undiagnosed recalcitrant pulmonary hypertension-management challenges.

We present two neonates requiring extracorporeal membrane oxygenation for undiagnosed recalcitrant pulmonary hypertension, highlighting the clinical and ethical dilemmas in management of very rare diseases.

Linked networks for learning and expressing location-specific threat.

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were "picked." Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or "bee sting"); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC-hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula-hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula-dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders.

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation.

The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-based navigation is impaired in pre-dementia Alzheimer's disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer's disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-based navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer's disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration performance correlated with Alzheimer's disease molecular pathology, with levels of CSF amyloid-ß and total tau contributing independently to distance error. Path integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer's disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer's disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer's drugs.

A culture of compassion: How timeless principles of kindness and empathy become powerful tools for confronting today's most pressing healthcare challenges.

The role of compassion in healthcare is receiving increased attention as emerging research demonstrates how compassionate patient care can improve health outcomes and reduce workplace stress and burnout. To date, proposals to encourage empathy, kindness, and compassion in healthcare have focused primarily on training individual care providers. This article argues that increasing the awareness and skills of individuals is necessary but insufficient. Compassionate care becomes an organizational norm only when health leaders create and nurture a "culture of compassion" that actively supports, develops, and recognizes the role of compassion in day-to-day management and practice. The article profiles four organizations that have adopted compassionate healthcare as an explicit organizational priority and implemented practical measures for building and sustaining a culture of compassion. Common principles and practices are identified. These organizations demonstrate how compassion can lead directly to improved outcomes of primary importance to healthcare organizations, including quality and safety, patient experience, employee and physician engagement, and financial performance. They show how compassion can be a powerful yet often underappreciated tool for helping organizations successfully manage current challenges.

High reliability in healthcare: creating the culture and mindset for patient safety.

Occurrences of patient harm in healthcare represent a significant burden, with serious implications for patients and families and for the capacity of health systems to manage patient access, flow, and wait times. Interest in the science of high reliability, developed originally in industries such as commercial airlines that have demonstrated exceptional safety records, is an emerging trend in healthcare with the potential to help organizations and systems achieve the ultimate goal of zero patient harm. This article argues that zero patient harm is a fundamental imperative, and that high-reliability science can help to accelerate and sustain progress toward this vital goal. Although the practices used in other industries are not readily transferable to healthcare, and no single proven model for High Reliability Organizations in healthcare is yet available, leading organizations are beginning to demonstrate effective healthcare-specific strategies. Experience from Studer Group's international network of partner organizations is used to illustrate and understand these early efforts. Studer Group's Evidence-Based LeadershipSM framework is applied in diverse healthcare settings to provide a foundation of culture transformation and change management to support high reliability. It offers an approach and resources for moving forward toward the goal of zero patient harm, with concurrent benefits related to the efficient use of our valuable healthcare resources.

La haute fiabilité en soins de santé: la création d'une culture et d'une mentalité favorisant la sécurité des patients.

Les préjudices que subissent les patients recevant des soins de santé représentent un fardeau considérable et peuvent avoir de graves répercussions sur les patients et les familles ainsi que sur la capacité des systèmes de santé de gérer l'accès des patients, leurs déplacements dans le système et les temps d'attente. L'intérêt pour la science de la haute fiabilité, mise au point à l'origine dans des secteurs comme l'aviation commerciale, qui ont un bilan exceptionnel en matière de sécurité, est une nouvelle tendance en soins de santé qui pourrait aider les organisations et les systèmes à atteindre le but ultime : zéro préjudice subi par les patients. Cet article fait valoir que zéro préjudice au patient est un impératif fondamental et que la science de la haute fiabilité peut aider à accélérer et à soutenir les progrès vers ce but vital. Bien que les pratiques utilisées dans d'autres secteurs ne soient pas facilement transférables aux soins de santé et qu'il n'existe pas encore un seul modèle éprouvé pour les organisations à haute fiabilité en santé, des organisations de premier plan commencent à faire la démonstration de stratégies efficaces propres aux soins de santé. L'expérience du réseau international d'organisations partenaires du groupe Studer est utilisée pour illustrer et comprendre ces premiers efforts. Le cadre Evidence-Based LeadershipSM (leadership fondé sur les données probantes) du groupe Studer est appliqué dans différents milieux de soins de santé pour transformer la culture et la gestion du changement visant à favoriser une haute fiabilité. Il propose une démarche et des ressources pour progresser vers le but zéro préjudice subi par les patients et tous les avantages liés à l'utilisation efficiente de nos précieuses ressources en soins de santé.

How vision and movement combine in the hippocampal place code.

How do external environmental and internal movement-related information combine to tell us where we are? We examined the neural representation of environmental location provided by hippocampal place cells while mice navigated a virtual reality environment in which both types of information could be manipulated. Extracellular recordings were made from region CA1 of head-fixed mice navigating a virtual linear track and running in a similar real environment. Despite the absence of vestibular motion signals, normal place cell firing and theta rhythmicity were found. Visual information alone was sufficient for localized firing in 25% of place cells and to maintain a local field potential theta rhythm (but with significantly reduced power). Additional movement-related information was required for normally localized firing by the remaining 75% of place cells. Trials in which movement and visual information were put into conflict showed that they combined nonlinearly to control firing location, and that the relative influence of movement versus visual information varied widely across place cells. However, within this heterogeneity, the behavior of fully half of the place cells conformed to a model of path integration in which the presence of visual cues at the start of each run together with subsequent movement-related updating of position was sufficient to maintain normal fields.

Impaired allocentric spatial processing in posttraumatic stress disorder.

A neurobiological dual representation model of PTSD proposes that reduced hippocampus-dependent contextual processing contributes to intrusive imagery due to a loss of control over hippocampus-independent sensory and affective representations. We investigated whether PTSD sufferers show impaired allocentric spatial processing indicative of reduced hippocampal functioning. Trauma-exposed individuals with (N=29) and without (N=30) a diagnosis of PTSD completed two tests of spatial processing: a topographical recognition task comprising perceptual and memory components, and a test of memory for objects' locations within a virtual environment in which the test is from either the same viewpoint as presentation (solvable with egocentric memory) or a different viewpoint (requiring allocentric memory). Participants in the PTSD group performed significantly worse on allocentric spatial processing than trauma-exposed controls. Groups performed comparably on egocentric memory and non-spatial memory for lists of objects. Exposure to repeated incident trauma was also associated with significantly worse spatial processing in the PTSD group. Results show a selective impairment in allocentric spatial processing, implicating weak hippocampal functioning, as predicted by a neurobiological dual representation model of PTSD. These findings have important clinical implications for cognitive therapy.

Extinction learning is slower, weaker and less context specific after alcohol.

Alcohol is frequently involved in psychological trauma and often used by individuals to reduce fear and anxiety. We examined the effects of alcohol on fear acquisition and extinction within a virtual environment. Healthy volunteers were administered alcohol (0.4g/kg) or placebo and underwent acquisition and extinction from different viewpoints of a virtual courtyard, in which the conditioned stimulus, paired with a mild electric shock, was centrally located. Participants returned the following day to test fear recall from both viewpoints of the courtyard. Skin conductance responses were recorded as an index of conditioned fear. Successful fear acquisition under alcohol contrasted with impaired extinction learning evidenced by persistent conditioned responses (Experiment 1). Participants' impairments in extinction under alcohol correlated with impairments in remembering object-locations in the courtyard seen from one viewpoint when tested from the other viewpoint. Alcohol-induced extinction impairments were overcome by increasing the number of extinction trials (Experiment 2). However, a test of fear recall the next day showed persistent fear in the alcohol group across both viewpoints. Thus, alcohol impaired extinction rather than acquisition of fear, suggesting that extinction is more dependent than acquisition on alcohol-sensitive representations of spatial context. Overall, extinction learning under alcohol was slower, weaker and less context-specific, resulting in persistent fear at test that generalized to the extinction viewpoint. The selective effect on extinction suggests an effect of alcohol on prefrontal involvement, while the reduced context-specificity implicates the hippocampus. These findings have important implications for the use of alcohol by individuals with clinical anxiety disorders.

Back to the future: Patient experience and the link to quality, safety, and financial performance.

Improving patient experience has emerged as an important healthcare policy priority across Canada. Tools and systems for monitoring patient experience metrics are becoming increasingly refined and standardized, and the trend toward greater accountability for improvements that are sustainable and affordable is well underway. For many healthcare professionals, this represents a renewed focus on core patient needs and priorities, following decades during which structural and technological changes have dominated healthcare agendas. Improving patient experience in our contemporary healthcare environment presents major challenges-and opportunities-for Canadian health leaders. The experience of Studer Group partner organizations in Canada is relevant and instructive in this context. These organizations have adopted a model known as Evidence-Based Leadership (EBL) that enables and supports the alignment of all activities and behaviours toward specific organizational goals, including measurable patient experience improvements. This article reviews case studies of organizations that have adopted EBL. These organizations are demonstrating rapid progress in patient experience indicators while simultaneously making gains in critical areas such as clinical outcomes, safety, physician and staff engagement, and financial performance. Emerging evidence concerning the factors and processes that underlie these improvements is also discussed.

Retour vers le futur: l'expérience des patients et le lien avec la qualité, la sécurité et le rendement financier.

Au Canada, l'amélioration de l'expérience des patients est devenue une priorité des politiques de santé. Le perfectionnement et la normalisation des outils et systèmes pour surveiller les mesures de l'expérience des patients augmentent, tandis que la tendance vers une plus grande reddition de compte sur des améliorations durables et abordables se confirme. Pour de nombreux professionnels de la santé, ce phénomène fait foi d'un intérêt renouvelé pour les besoins et priorités fondamentaux des patients, après des décennies où les changements structurels et technologiques ont dominé les programmes de santé. Pour les leaders en santé canadiens, l'amélioration de l'expérience des patients comporte actuellement de grands défis et de belles possibilités. À cet égard, l'expérience des organisations partenaires du groupe Studer au Canada est à la fois pertinente et instructive. Ces organisations ont adopté un modèle, du nom de Evidence-Based Leadership (EBL, ou leadership fondé sur des données probantes), qui favorise et soutient l'harmonisation de l'ensemble des activités et des comportements, conformément à des objectifs organisationnels précis, y compris des améliorations mesurables de l'expérience des patients. Le présent article expose des études de cas d'organisations qui ont adopté l'EBL. Ces organisations ont réalisé des progrès rapides en matière d'indicateurs de l'expérience des patients, ainsi que dans des secteurs essentiels comme les résultats cliniques, la sécurité et le rendement financier. Les données émergentes sur les facteurs et processus qui sous-tendent ces améliorations sont également abordées.

Contextual memory, psychosis-proneness, and the experience of intrusive imagery.

This study tested the hypothesis that the presence and characteristics of naturally occurring involuntary imagery would be related to poorer context-dependent spatial memory and higher levels of proneness to psychotic experiences. Poorer contextual memory was also predicted to be associated with a greater sense of "nowness". Participants completed a virtual environment task that assessed contextual memory through responses that required allocentric and egocentric processing of virtual stimuli. Two questionnaires assessing predisposition to psychotic experiences were employed. Finally, participants completed an interview that required details of recent, naturally occurring involuntary images. Reports of involuntary imagery were associated with greater proneness to psychotic experiences but not with memory. In those participants who reported imagery, however, poorer memory performance was associated with more vivid and detailed intrusive imagery. Poorer contextual memory was specifically associated with a greater sense of "nowness". Possible links between contextual memory and proneness to psychosis are discussed.

An Update on CFTR Modulators as New Therapies for Cystic Fibrosis.

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

Impaired allocentric spatial memory in patients with affective disorders.

BACKGROUND: Memory disturbances are frequent in unipolar depression (UD) and bipolar disorder (BD) and may comprise important predisposing and maintaining factors. Previous studies have demonstrated hippocampal abnormalities in UD and BD but there is a lack of studies specifically assessing hippocampus-dependent memory. METHODS: We used a virtual task to assess hippocampus-dependent (allocentric) vs non-hipppocampal (egocentric) spatial memory in remitted and partially remitted patients with UD or BD (N = 22) and a healthy control group (N = 32). Participants also completed a range of standard neuropsychological and functional assessments. RESULTS: Participants in the UD/BD group showed selective impairments on high-load hippocampal (allocentric) memory compared to egocentric memory and this effect was independent of residual mood symptoms. Across both samples, both allocentric and egocentric spatial memory correlated with more general measures of memory and other aspects of cognition measured on standard neuropsychological tests but only high-load allocentric memory showed a significant relationship with functional capacity. CONCLUSION: Results show a selective impairment in high-load allocentric spatial memory compared to egocentric memory in the patient group, suggesting impaired hippocampal functioning in patients with remitted UD/BD.

Establishing the boundaries: the hippocampal contribution to imagining scenes.

When we visualize scenes, either from our own past or invented, we impose a viewpoint for our "mind's eye" and we experience the resulting image as spatially coherent from that viewpoint. The hippocampus has been implicated in this process, but its precise contribution is unknown. We tested a specific hypothesis based on the spatial firing properties of neurons in the hippocampal formation of rats, that this region supports the construction of spatially coherent mental images by representing the locations of the environmental boundaries surrounding our viewpoint. Using functional magnetic resonance imaging, we show that hippocampal activation increases parametrically with the number of enclosing boundaries in the imagined scene. In contrast, hippocampal activity is not modulated by a nonspatial manipulation of scene complexity nor to increasing difficulty of imagining the scenes in general. Our findings identify a specific computational role for the hippocampus in mental imagery and episodic recollection.

Parallel striatal and hippocampal systems for landmarks and boundaries in spatial memory.

How the memory systems centered on the hippocampus and dorsal striatum interact to support behavior remains controversial. We used functional MRI while people learned the locations of objects by collecting and replacing them over multiple trials within a virtual environment comprising a landmark, a circular boundary, and distant cues for orientation. The relative location of landmark and boundary was occasionally changed, with specific objects paired with one or other cue, allowing dissociation of learning and performance relative to either cue. Right posterior hippocampal activation reflected learning and remembering of boundary-related locations, whereas right dorsal striatal activation reflected learning and remembering of landmark-related locations. Within the right hippocampus, anterior processing of environmental change (spatial novelty) was dissociated from posterior processing of location. Behavioral studies show that landmark-related learning obeys associative reinforcement, whereas boundary-related learning is incidental [Doeller CF, Burgess N (2008) Proc Natl Acad Sci USA 105:5909-5914]. The distinct incidental hippocampal processing of boundaries is suggestive of a "geometric module" or "cognitive map" and may explain the hippocampal support of incidental/observational learning in "declarative" or "episodic" memory versus the striatal support of trial-and-error learning in "procedural" memory. Finally, the hippocampal and striatal systems appear to combine "bottom-up," simply influencing behavior proportional to their activations, without direct interaction, with "top-down" ventromedial prefrontal involvement when both are similarly active.

Location-dependent threat and associated neural abnormalities in clinical anxiety.

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment.

ERS International Congress 2020: highlights from the Paediatric Assembly.

In this review, the Paediatric Assembly of the European Respiratory Society (ERS) presents a summary of the highlights and most relevant findings in the field of paediatric respiratory medicine presented at the virtual ERS International Congress 2020. Early Career Members of the ERS and Chairs of the different Groups comprising the Paediatric Assembly discuss a selection of the presented research. These cover a wide range of research areas, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis, respiratory infection and immunology, neonatology and intensive care, epidemiology, bronchology and lung and airway development. Specifically, we describe the long-term effect in lung function of premature birth, mode of delivery and chronic respiratory conditions such as cystic fibrosis. In paediatric asthma, we present risk factors, phenotypes and their progression with age, and the challenges in diagnosis. We confirm the value of the lung clearance index to detect early lung changes in cystic fibrosis. For bronchiectasis treatment, we highlight the importance of identifying treatable traits. The use of biomarkers and genotypes to identify infants at risk of long-term respiratory morbidity is also discussed. We present the long-term impact on respiratory health of early life and fetal exposures to maternal obesity and intrauterine hypoxia, mechanical ventilation hyperoxia, aeroallergens, air pollution, vitamin A deficient intake and bronchitis. Moreover, we report on the use of metabolomics and genetic analysis to understand the effect of these exposures on lung growth and alveolar development. Finally, we stress the need to establish multidisciplinary teams to treat complex airway pathologies.

Arresting visuospatial stimulation is insufficient to disrupt analogue traumatic intrusions.

Intrusive memories are a core symptom of Post-Traumatic Stress Disorder (PTSD). A growing body of analogue studies using trauma films suggest that carrying out specific demanding tasks (e.g., playing the video game Tetris, pattern tapping) after the analogue trauma can reduce intrusive memories. To examine the mechanism behind this effect, we tested whether mere engagement with attention-grabbing and interesting visual stimuli disrupts intrusive memories, and whether this depends on working memory resources and/or the concurrent activation of trauma film memories. In a total sample of 234 healthy participants, we compared no-task control conditions to a perceptual rating task with visually arresting video clips (i.e., non-emotional, complex, moving displays), to a less arresting task with non-moving, blurred pictures (Study 1), and to more demanding imagery tasks with and without repetitive reminders of the trauma film (Study 2). Generally, we found moderate to strong evidence that none of the conditions lead to differences in intrusion frequency. Moreover, our data suggest that intrusive memories were neither related to individual differences in working memory capacity (i.e., operation span performance; Study 1), nor to the degree of engagement with a visuospatial task (i.e., one-week recognition performance; Study 2). Taken together, our findings suggest that the boundary conditions for successful interference with traumatic intrusions may be more complex and subtle than assumed. Future studies may want to test the role of prediction errors during (re-)consolidation, deliberate efforts to suppress thoughts, or the compatibility of the task demands with the individual's skills.

Neural bases of autobiographical support for episodic recollection of faces.

Incidental retrieval of autobiographical knowledge can provide rich contextual support for episodic recollection of a recent event. We examined the neural bases of these two processes by performing fMRI scanning during a recognition memory test for faces that were unfamiliar, famous, or personally known. The presence of pre-experimental knowledge of a face was incidental to the task, but nonetheless resulted in improved performance. Two distinct networks of activation were associated with correct recollection of a face's prior presentation (recollection hits vs. correct rejections) on one hand, and with pre-experimental knowledge about it (famous or personally known vs. unfamiliar faces) on the other. The former included mid/posterior cingulate cortex, precuneus, and ventral striatum. The latter included bilateral hippocampus, retrosplenial, and ventromedial prefrontal cortices. Anterior and medial thalamic activations showed an interaction between both effects, driven by increased activation for recollection of unfamiliar faces. When recollecting the presentation of a famous or personally known face, hippocampal activation increased with participants' ratings of how well they felt they knew the person shown. Ventromedial prefrontal cortex showed significantly greater activation for personally known than famous faces. Our results indicate a dissociation between the involvement of retrosplenial vs. mid/posterior cingulate and precuneus in memory tasks. They also indicate that, during recognition memory experiments, the hippocampus supports incidental retrieval of pre-experimental knowledge about the stimuli presented. This type of knowledge likely underlies the additional recollection found for prior presentation of well known stimuli compared with novel ones and may link hippocampal activation at encoding to subsequent memory performance more generally.