Co-occurring medical disorders and associated physiological abnormalities in individuals with autism spectrum disorder (ASD) may provide insight into causal pathways or underlying biological mechanisms. Here, we review medical conditions that have been repeatedly highlighted as sharing the strongest associations with ASD—epilepsy, sleep, as well as gastrointestinal and immune functioning. We describe within each condition their prevalence, associations with behavior, and evidence for successful treatment. We additionally discuss research aiming to uncover potential aetiological mechanisms. We then consider the potential interaction between each group of conditions and ASD and, based on the available evidence, propose a model that integrates these medical comorbidities in relation to potential shared aetiological mechanisms. Future research should aim to systematically examine the interactions between these physiological systems, rather than considering these in isolation, using robust and sensitive biomarkers across an individual's development. A consideration of the overlap between medical conditions and ASD may aid in defining biological subtypes within ASD and in the development of specific targeted interventions. Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental conditions characterized by reduced social interaction and communication, as well as restricted range of interests and/or stereotypic behaviors , 2. ManyPrevalence estimates of medical comorbidities vary greatly depending on the population studied. One of the largest studies of hospital records of children and young adults with ASD in the US found that prevalence estimates of a range of co-morbid disorders, particularly gastrointestinal and seizure disorders, greatly exceeded that compared to the general hospital population . Other sThere have been several reviews and empirical studies focusing on specific medical, e.g., –17], beh, beh17)]Epilepsy, defined as two unprovoked seizures of any type, can be extended out to include multiple disorders with various etiologies, pathophysiology and outcomes . PrevaleAll seizure types appear to be associated with ASD but vary in prevalence depending on the population studied  compared to those without comorbid intellectual disability (8%) , as wellA diagnosis of comorbid epilepsy and ASD is a negative prognostic indicator, associated with greater risk of poorer outcomes . ChildreAs epilepsy may contribute to elevated mortality rates in ASD, appropriate detection and treatment of elevated seizure activity in individuals with ASD is a clear and urgent treatment need ; see Tab. TreatmeSeizure disorders can be due to many causes, including acute or chronic focal or diffuse brain pathology, genetic mutations, metabolic causes, or idiopathic reasons; as such, attempts to identify common causal pathways between ASD and epilepsy have proven to be a complex endeavor. While a number of reports have suggested common neuropathology in children with ASD and epilepsy , the vasMany candidate genes associated with ASD and epilepsy are involved in synaptic formation and maintenance  and GABAergic neurotransmission . The poThe association between genetic disorders, epilepsy and ASD could provide a further indication of the aetiological mechanisms underlying ASD and epilepsy . GeneticDespite many common associations found in both disorders, there is a limited amount of evidence investigating shared environmental and/or neuroinflammation pathways leading to comorbid epilepsy and ASD, for example advanced maternal/paternal age  or increThe well-documented overlap between ASD and epilepsy points toward shared aetiological mechanisms. Current findings do not suggest a causative role for epilepsy and abnormal epileptiform activity in the development of ASD; rather, presence of comorbid conditions predicts poorer prognostic outcome in individuals, and as such, indicates need for greater monitoring and interventions for associated factors. Research to date has not yet been able to fully determine the anatomical or molecular causes of why these conditions converge, as it is difficult to distinguish the effects of the underlying pathology from the neurological effects of the seizures themselves .Sleep problems occur in a significantly higher proportion of children with ASD compared to typically developing children and children with other developmental delays . PrevaleA range of sleep disorders may be present in children with ASD, including insomnia , sleep disordered breathing , parasomnias , and sleep related movement disorders . Using parental reports, Goldman and colleagues found that younger children with ASD experienced more sleep anxiety, bedtime resistance, night wakefulness, and parasomnias; adolescents, however, tended to have more difficulty falling asleep, getting enough sleep, and experiencing daytime sleepiness . ActigraSleep has a vital role to play in child development as it serves multiple functions, such as energy conservation, brain growth, cognition and memory consolidation . The relSleep disorders may be caused by core ASD symptoms; for example, children may have reduced sensitivity to environmental cues that help signal the sleep/wake circadian systems, perseverate on activities or thoughts that may interfere with sleep onset or promote nocturnal awakenings, have limited communication to understand parental expectations for bedtime, or have more challenging behaviors such as hyperactivity or environmental hypersensitivities that may preclude ability to settle down to sleep . HoweverRates of co-occurring ASD and ADHD are also high, with the prevalence of ADHD symptoms in individuals with ASD ranging from 40 to 70% . The keyPotential treatments for sleep disturbances range from behavioral to pharmacological, with the goal to not only improve sleep quality and daytime functioning but also reduce caregiver stress . AlthougConversely, it has also been argued that medications often prescribed to treat symptoms such as anxiety in individuals with ASD may negatively influence sleep. For example, it has been suggested that anti-psychotics and serotonin reuptake inhibitors (SSRIs) may disrupt the sleep cycle and thus have a role to play in sleep disorder . Some meDevelopment of a circadian rhythm has a vital role to play in the development of a competent sleep cycle, controlling different biological rhythms within a 24-h period and modified by both internal and external factors. It is thought that this rhythm regulates both biological and behavioral functions and how an individual can anticipate and adapt to environmental changes . When thGenes known to be associated with the human circadian clock have an important role to play in controlling sleep phase and duration  and haveCurrent findings suggest that sleep disorders in children with ASD may be associated with altered circadian rhythms, which may reflect mutations in clock genes and genes involved in melatonin production. Furthermore, sleep disorders in ASD have been associated with behavioral and psychiatric co-morbidities, such as anxiety or ADHD. The directional impact of these underlying mechanisms remains complex when additionally considering the impact of pharmacological interventions, however the broader evidence based suggests co-occurrence of sleep problems with behavioral symptoms, rather than an aetiological mechanism.Estimates for the prevalence of any gastrointestinal (GI) problem in children with ASD vary between 9 and 70% , 123, buIt has been speculated that underlying and undiagnosed GI problems may contribute to some of the behavioral difficulties observed in some children with ASD. Chaidez et al.  suggesteA wide range of diets have been purported to exert some efficacy in alleviating GI symptoms in children with ASD. However, a systematic review found little evidence for the beneficial effect of nutritional supplements or gluten/casein-free diets on ASD symptoms . FurtherMicrobiota transfer therapy has recently been suggested as a potential therapy in ASD to target GI symptoms based on the premise of differences in microbiome composition . HoweverThe underlying mechanism of GI dysfunction and how this relates to the pathophysiology of ASD is still not well understood. One theory in particular has gained particular momentum, that abnormal neurodevelopment in ASD may be caused by increased GI permeability, so-called “leaky gut,” that facilitates the absorption of toxic by-products of incompletely digested proteins [see  for reviSerotonin is critical for gut function, with 80–95% of 5-HT receptors localized to the gut and alterations to 5-HT signaling related to many GI disorders . It has been speculated that altered gut 5-HT signaling may be an important contributor to the presence of GI disorders in children with ASD , 150; a Increasing evidence suggests GI complications can arise as a result of genetic and environmental risk factors for ASD. For example, variants in the c-Met gene encoding for MET receptor tyrosine kinase are associated with ASD in individuals with co-occurring GI dysfunction . The rolDysfunctional immune responses (see section Immune Dysfunction), in particular mucosal immune cells, may also have adverse effects on GI functioning in ASD. Endoscopic investigations suggest diffuse inflammation in the intestinal tract of children with ASD . There hIndividuals with ASD are at higher risk of experiencing GI disturbances, with GI problems further linked to increased ASD symptoms. Abnormal neurodevelopment, dysfunctional immune responses and altered serotonergic transmission have been suggested potential mechanisms underlying the overlap between ASD and GI dysfunction.The immune system comprises a group of defense mechanisms triggered to protect against disease or illness causing pathogens. Antigens, proteins found on the surface of pathogens, are recognized by a healthy immune system and trigger the production of antibodies that identify and neutralize or remove the antigen. The immune system comprises both innate and adaptive systems. The innate system develops early in fetal development, using genetically encoded receptors and nonspecific mechanisms for defense. In this way, the innate system plays more of a “housekeeping” role. The adaptive system is responsible for threat response, developing a memory of the response for future threats, and does not fully mature until early childhood. This system is more dynamic, responding to potential pathogens and toxins upon exposure. Both systems work together to achieve homeostasis, and importantly, disruption in either can affect neuronal development and functioning . OptimalPrevalence of immune conditions in individuals with ASD varies considerably between studies. Increased rates of food allergies, allergic rhinitis, and atopic dermatitis  , 172, asAn extension of this research is the question of whether changes in peripheral cytokine expression are associated with differences in individual behaviors within individuals with ASD. If so, this would then suggest that interventions that target the immune system might have some benefit in improving symptoms. Chemokine levels have been associated with impaired communication, increased parent-reported behavior problems, decreased cognitive and adaptive functions, and worse adaptive behavior . IncreasThere is some preliminary evidence for cytokine changes in response to medical treatments in ASD. Choi et al. showed that levels of some cytokines significantly reduced after risperidone treatment in children with ASD, and interleukin 5 was specifically increased in a small sample of treatment responders . HoweverImmune-modulatory agents have also been trialed to specifically target ASD symptoms . SignifiThe mechanisms by which dysfunctional immune systems may contribute etiologically to ASD is an area of active investigation . Here, wIn addition to examining diagnosed immune conditions, significant research has focused on measurements of cytokine signaling profiles as indicators of broader changes in inflammatory processes in individuals with ASD . CytokinA recent meta-analysis of cytokine levels derived from plasma and serum in unmedicated individuals with ASD (mostly children) found an overall abnormal cytokine profile, characterized by elevations in proinflammatory cytokines and reduced levels of anti-inflammatory cytokines . This suOne well-researched area has explored early maternal infection and inflammation during pregnancy and later risk for an ASD diagnosis –225. PreDisruptions in both innate and adaptive immunity have clear consequences for neurodevelopment, with the cumulative evidence suggestive of a disrupted immune profile in for some individuals with ASD as well as links to the early maternal pregnancy environment in shaping later immune profiles and neurodevelopment. There evidence to suggest a direct association between perturbed immune profiles and impact on subsequent behavioral and symptomatic profiles, with limited studies for potential changes in immune profiles in response to treatment or changes in immune functioning through anti-inflammatory markers to facilitate reductions in core ASD symptoms. Taken together, this evidence suggests that an immune-mediated subtype of ASD may be amenable to specific, targeted and/or personalized treatments based on individual immune profiles.This review highlights that the interactions between observed comorbid medical conditions and physiological abnormalities in children with ASD are complex. Disorders of GI function and seizures appear to be parallel comorbid conditions, with possible common aetiological mechanisms resulting from yet unknown neurological causes. Sleep disorders, however, are likely to be a consequence of ASD symptoms or may be, in turn, associated with GI symptoms or other comorbidities that can cause sleep disturbances. Whilst the evidence discussed suggests a causative role for metabolic and immunological pathways for some individuals later diagnosed with ASD, evidence for these remains preliminary and based on group level findings, rather than evidence from prospective and longitudinal observations. What is clear, however, is that these systems and pathways do not work in isolation from each other; rather, complex interactions imply dysregulation in any one system may cause a cascade of events cumulating in a cluster of symptoms associated with ASD Figure . BecauseAs discussed in each section, complicating interactions between these systems suggest a greater likelihood for individuals with alterations in one system to have alterations across multiple systems. Still, the overlap between medical and behavioral features associated with ASD may point toward convergent platforms for a final common pathway to ASD across varied causes, with implications for targeted treatment. For example, children who have sleep problems and ASD are two times more likely to have GI issues and seizures .Review of the proposed aetiological mechanisms underlying the comorbidity between these medical comorbidities and ASD allows some degree of integration. Processes with shared involvement in ASD and multiple medical disorders include gene transcriptional regulation; cellular growth and proliferation; and synapse development, stability and function. Importantly, the potential role of the microbiota-gut-brain axis in multiple elements of medical comorbidity has been implicated Figure , wherebyAssociations between sleep and other disorders are also apparent; while classically functioning to regulate circadian and seasonal rhythms, melatonin additionally affects cardiovascular and immune systems, regulates body fat mass, insulin secretion, and metabolism of glucose and lipids, as a close derivative of serotonin (5-HT). Due to these additional functions, emerging research has highlighted a role for melatonin administration in humans to attenuate metabolic symptoms induced by antipsychotic use  and to pSimilarly, comorbid medical conditions and associated medication use may result in sleep disturbance; for example, physical symptoms such as abdominal pain in some GI disorders, or medications prescribed for seizures can cause difficulty sleeping. Children with epilepsy also exhibit significant alterations in sleep latency, sleep efficiency, and number of awakenings , and epiFinally, alterations in immune system profiles, dysregulated gastrointestinal symptoms and disordered sleep patterns clearly impact upon behavioral profiles, including elevated anxiety, increased social and communication difficulties, reduced adaptive functioning, and increased maladaptive behaviors. Recent meta-analytic evidence confirms an association between sleep disturbances and increased inflammation, suggesting that improvements in one system could potentially positively impact upon other regulatory systems . GeneratA key aim for future research will be to examine the interactions between these systems using established biomarkers along their pathways within ASD, rather than examining each in isolation Box . PossiblBox 1- Using expertise from a diverse range of disciplines—genetics, neuroscience, biochemistry and developmental psychology—to disentangle biological mechanisms underpinning medical comorbidity.- Improved understanding of the link between comorbid medical conditions and co-occurring mental health problems and psychopathology in ASD.- Understanding the longitudinal course of the full range of medical comorbidities in ASD.- Treatment and intervention studies to systematically assess whether treating medical issues has additional positive effects on other medical issues  or on behavioral domains.An important consideration is the time at which symptoms or markers are assessed. As a developmental condition, the symptoms of ASD change over the course of the child's lifespan, and there is increasing acknowledgment for the importance in understanding an individual's trajectory over time to grasp the full complexity of the heterogeneous symptoms presentations within ASD . CurrentAssessment of co-occurring medical problems is of critical importance in the initial diagnostic procedure for individuals with ASD as well as in ongoing treatment management. As part of a multidisciplinary approach, systematic and evidence-based screening should be recommended at the time of diagnostic evaluations as well as during ongoing health monitoring. A key conclusion from this review is the importance of monitoring and maintaining general health and wellbeing in individuals with ASD. Although many of the medical conditions or abnormalities may not be present in many individuals with ASD, the overall increased risk of all-cause mortality in this population indicates a need for increased vigilance. For example, comorbid epilepsy, particularly accompanied by intellectual disability, is associated with an increased mortality risk; thus, there is a significant imperative for clinicians and parents/careers to provide additional care and monitoring around overall health and wellbeing for these individuals to potentially attenuate this risk. Cumulative evidence highlights increased prevalence of obesity and poor diet in individuals with ASD, and decreased use of general health services, such as for oral health, due to barriers to accessing health care that supports individuals with special needs. There is also a critical need for healthcare services to provide supportive and accessible environments for individuals with ASD.The burden of such medical conditions in increasing mortality is likely compounded by impaired communication and increased sensory sensitivities that present a significant barrier to the delivery of health care services (both preventative and targeted treatment). A growing area of research has therefore focused on the necessity for effective and targeted health care services that are designed for ASD, as well as identifying potential barriers to access and use . ApproprThe presence of comorbid medical conditions in ASD highlights the vast heterogeneity within the disorder. Using a model-based approach to understand the interacting systems potentially involved in the etiology and symptoms of ASD may lead to hypothesis generation and potential avenues for clinical trials. We require a better understanding of how variability in these systems results in similar or different functional profiles in ASD, and more integrative studies that consider the interaction between systems and the environment to produce behaviors characteristic of ASD. Such an approach can then lend hope to more specific biomedical treatments aimed at targeted these biomedical abnormalities and improving core and associated symptoms in ASD, ultimately to improve long-term outcomes.CT and GA led in the conception and design of the review. CT, AR, and GA drafted the paper. AW provided substantial revision.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Memories are about the past, but they serve the future. Memory research often emphasizes the former aspect: focusing on the functions that re-constitute (re-member) experience and elucidating the various types of memories and their interrelations, timescales, and neural bases. Here we highlight the prospective nature of memory in guiding selective attention, focusing on functions that use previous experience to anticipate the relevant events about to unfold—to “premember” experience. Memories of various types and timescales play a fundamental role in guiding perception and performance adaptively, proactively, and dynamically. Consonant with this perspective, memories are often recorded according to expected future demands. Using working memory as an example, we consider how mnemonic content is selected and represented for future use. This perspective moves away from the traditional representational account of memory toward a functional account in which forward-looking memory traces are informationally and computationally tuned for interacting with incoming sensory signals to guide adaptive behavior. Nobre and Stokes consider how memories guide proactive attention. Introducing the concept of premembering, this perspective advances a functional account of memory. Memory traces are informationally and computationally tuned for interacting with incoming sensory signals to guide adaptive behavior. BOX 1“Cognitive control” refers to the collection of mechanisms that set and adjust our goals and that monitor and regulate performance according to competing demands. Thus, the selective attention mechanisms we review are subordinate to cognitive control, prioritizing and selecting putative targets and overcoming irrelevant distraction within a particular goal setting. Memories are increasingly recognized to play an important role in influencing the degree of top-down control exerted on a given trial. They include both short-term traces between successive trials as well as intermediate memory traces that develop over task performance .“Decision-making” refers to the process of choosing one of a set of alternatives to produce a beneficial outcome. Choices are made based on expectation of rewards developed through previous experience. Current models of decision-making mostly rely on reinforcement learning. Recent computational studies suggest that different types of memory traces may work together to optimize reinforcement learning, including those resulting from slow incremental implicit learning over trials as well as episodic traces uniquely linked to individual experiences .“Decision-making” is closely related to selective attention, which can be involved in prioritizing information for guiding choice behavior. Expectations play an essential role in both sets of processes. However, interestingly, they each stress a different consequence of prior knowledge. In decision-making, predictions based on priors are mainly used to attenuate the processing of what can be anticipated . In sele“Episodic future thinking” involves drawing on previous experiences to imagine oneself in future situations . The conWe focus on how memories guide selective attention. The role memory plays in guiding behavior has also been considered within other cognitive domains.Memory’s most compelling illusion is that it represents the past. However, it is clear from an ecological perspective that memory is all about the future. The purpose of memory is to learn about the environment to anticipate future demands—not just putting back the pieces of the past for recollection (remembering experience) but deriving possibilities based on the past to guide future adaptive behavior (premembering experience). This notion has old roots , but, suSelective attention  refers to the set of functions that prioritize and select information to guide adaptive behavior . These fThe premembering perspective has important implications for understanding the content and formatting of memory. Rather than slavishly storing and using veridical traces, the brain flexibly selects and even distorts memory content to enhance its utility in guiding attention. Moreover, task-relevant informational content may also be stored in a neural format that is optimized for the anticipated utilization of the memory to guide performance.The essence of memory is the traces left by passing experience. These range from transient perturbations to engrams that last a lifetime, capturing modality-specific fragments to relational and integrated wholes and supporting unconscious states to recollective phenomena. Such traces can provide essential informational content required for prospectively prioritizing and selecting what is important. Working together, memory content and attention functions shape how the brain transforms incoming signals to guide perception, choice, action, and the formation of new memories to serve adaptive behavior in the future . It can Drawing a clear line defining when present becomes past may be impossible. Nevertheless, it is clear that past traces affect perception even from their earliest moments. The very stitching of visual perception across eye movements into an apparent cohesive flow may rely on short-term memories bridging the anchoring and landing fixation contents . FurtherAt slightly longer timeframes, WM provides a limited set of more durable traces that are independent of continuous sensory stimulation and resistant to interference and that act to guide adaptive behavior . The funMoreover, beyond the scope of classic WM, the relation between successive items can also influence information processing. For example, when searching for an odd-one-out target, its identification is facilitated when the current target shares a defining feature value  or locatShort-term memory traces can be used to enhance or suppress information processing, depending on the situation. For example, after initial facilitation of stimuli in the wake of non-informative salient stimuli, decrements in performance occur at the same location; the “inhibition of return” has been proposed to encourage sampling and exploration . Pre-expAlthough most research has focused on the role of short-term traces in anticipatory attention, the memory traces that guide our perception stretch further back in time. Most of the knowledge that guides the interpretation of sensory signals and sets up expectations about the occurrence and context of relevant events is stored in our long-term memory LTM; . HoweverIncreasing numbers of experimental approaches are beginning to explore how different types of intermediate traces guide attention within task settings. “Probability cueing” refers to performance benefits resulting from the higher prevalence of a task-relevant item within a given location . The fre“Reward history,” referring to the likelihood or value of a reward typically associated with given target stimuli within a task, has strong and persistent effects on performance . Reward Learning and utilization of more complex associations also occur within task settings. “Contextual cueing” shows that pick-up of repeated spatial configurations of stimuli within visual search arrays facilitates target identification . This tyAlthough the role of LTM in guiding attention has been less well explored than that of WM, its fundamental role in defining perception, choosing actions, imagining, and forming new memories has long been recognized ; Box 1. In everyday situations, the bank of remote memory traces from previous settings and episodes arguably provides the richest source of information for guiding attention and perception. When waiting to meet a friend on a busy street, we rely on LTM to search them out based on their appearance and likely route. LTM provides knowledge about whether and how relevant events occur in particular contexts and about their likely reward outcome values. Thus, they afford rich content for flexible, proactive, and dynamic biases to guide the prioritization and selection of relevant information . An incrIn visual search tasks using simple stimulus arrays, semantic knowledge of features commonly associated with objects facilitates target identification, overcoming usual costs associated with feature binding . On the In tasks using complex scenes or environments, “contextual priming” studies show that previous experiences within particular contexts guide the identification and interpretation of objects within the same contexts . When seMemory-guided attention tasks show how learning of object locations through repeated visual search in complex scenes or environments facilitates performance in subsequent tasks. Performance measures reveal significant improvements in detecting and discriminating target items as a result of previously learned specific contextual association between the particular item and a scene or three-dimensional environment .“Memory-guided orienting” tasks provide a good platform to investigate anticipatory biases based on long-term memories C. ParticThus, findings with memory-guided orienting tasks clearly illustrate the ability of the brain to use LTM content proactively to guide prioritization and suggest the involvement of limbic, memory-related circuits. In monkeys, recent studies recording activity from neurons in the hippocampus and entorhinal cortex during free viewing provide converging evidence that medial temporal areas, traditionally associated with memory, are closely related to attention. Neurons in the entorhinal cortex show strong visuospatial coding properties, signaling gaze location using multiple frames of reference . EntorhiIn addition to carrying information about the location and identifying attributes of anticipated events, memory traces also carry information about their timing. Memory-based temporal expectations can therefore enable the brain to prepare for events in a dynamic, temporally structured, and efficient way . TemporaRecognizing that memory traces of different types and timescales proactively guide perception invites us to reconsider dominant concepts and dichotomies in the attention literature. The simple separation between “bottom-up” sources of prioritization based on physical salience and “top-down” sources based on current goals is clearly insufficient. To explore the natural kinds of memory-based attention, it is important to separate two fundamental factors: their volitional character and their source.Subjectively, attention can be voluntary or involuntary, and its source can be external, based on physical salience (exogenous), or internal, based on brain states linked to current goals or previous experience (endogenous). Often these two factors are conflated, with exogenous sources assumed to guide involuntary attention and endogenous sources assumed to guide voluntary attention. Instead, they should be viewed as theoretically separable. Although physically salient stimuli capture attention involuntarily, endogenous sources can guide attention both voluntarily and involuntarily. In addition to their use in goal-based voluntary attention, both short-term as well as LTM sources can also have automatic, involuntary consequences for perception. For example, short-term memory carrying goal-related information to perform one task also inadvertently influences performance in another task, sometimes causing significant interference . Memory In recognizing the role that memory associations within task settings play in attention, some contemporary models of attention have proposed adding a third, “history” source to the traditional bottom-up and top-down sources in attention e.g., . The incThe internal, memory-based sources of attention are many. Memories of various durations and types contribute, from traces that stitch the continuity of perception to those that guide the recognition of a long-lost friend. Most likely, multiple memory systems and mechanisms are involved. For example, both contextual cueing and memory-based orienting involve LTM for the location of a target object within a given configuration in an array or scene, and in both cases, the medial-temporal areas have been implicated. However, brain imaging shows increased hippocampal activity during memory-guided orienting in scenes  and decrThus, the literature suggests a rich diversity of mnemonic influences on attention, with at least some functional dissociations. There is much empirical work ahead to reveal the natural kinds and neural mechanisms of memory-based attention to derive its principles of organization and develop useful theoretical models. Traces of different kinds and durations could act separately and largely independently; they could compete, they could become integrated within a unified predictive model  was largely dominated by the single relevant item of a multi-item array during a selective delayed-match-to-sample task . Later, Selectivity in WM is also well documented in the human brain. The CDA marker of WM derived from electroencephalograms (EEGs) shows that encoding can be spatially and item selective e.g., . In addiStudies in human participants have also demonstrated that selective contents in WM can be updated flexibly as predictions change about the items or features that will be relevant for task performance . Cues prFrom a functional perspective, it is not always optimal simply to maintain a veridical representation of previous input. When making some types of fine-grained delayed discriminations, it can be more advantageous to focus on neural information tuned away from the behaviorally relevant feature to maximize separability from distractor items . In suchThese studies clearly reveal the prospective face of WM: content is optimized to the expected demands of future processing. In some cases, the prospective WM representation triggered by a stimulus bears no physical resemblance to it. WM representations also go beyond the experienced stimulus to construct motor representations when specific actions can be anticipated. Most WM tasks tend to probe the perceptual content of the memoranda and typically isolate perceptual qualities of stimuli from particular responses. In everyday life, however, the perceptual content of WM often also carries motor affordances, such as when reaching out and grasping the cup of coffee outside your field of view or repeating a telephone number to a friend. In a recent visual WM task that linked the reporting of particular stimulus orientations to a specific hand, it became clear that motor representations are derived from visually encoded stimuli and that motor information is in a similar state of readiness as visual content when participants are probed D.The prospective attributes of LTM are much more difficult to study. Except under highly constrained experimental conditions, it is difficult to determine what aspects of experience will prove useful to guide future behavior at distant time points. Nevertheless, the prospective nature of LTM can be gleaned from a few observations. The content of LTM is selective. We better remember items that were relevant during the encoding context . We retaWhen considering the prospective nature of memory, studies have typically focused on the task dependency of the representational content (as reviewed above). This information-based perspective provides an important starting point. At minimum, the content of memory provides the basic information needed for adaptive guidance of preparatory attention. However, we need to delve deeper to understand how memories proactively exert their influence in adaptive behavior. Focusing specifically on WM, we consider how mnemonic states functionally contribute to memory-dependent processing of subsequent input.From a functional perspective, we can distinguish the task relevance of specific types of information from their intended use . For exaTheoretical simulations suggest that WM may be coded differently depending on expected future use. The extant empirical data are also consistent with the theoretical proposal that the format of WM depends on expected use. For example, If computational specificity is functionally relevant to future processing and also inherent to WM, then we might predict that the content of WM always guides attention. The evidence for this hypothesis is mixed. In a series of behavioral and neuroimaging studies, To reconcile the apparent contradiction, Active and latent memories can be studied more directly by experimentally manipulating the relative priority of items in WM using retro-cues . BehavioIt is tempting to think of retro-cueing simply as an internal spotlight boosting the representational content of cued relative to uncued  memoranda. However, we argue that retro-cues may also transform the format of a memorandum, preparing it for future use, such as by placing it in a prioritized state and linking its informational content to future action . MoreoveHuman neurophysiology also supports the general view that prioritizing an item in WM involves a discrete state transition  rather tRecent brain imaging studies also identified different neural correlates of WM depending on current priority status. There is a quantitative difference in decodability between active and latent items. Across multiple experiments, These decoding studies show that latent working memories can be nearly impossible to detect in delay period activity. Nevertheless, complementary recent evidence shows that latent memories may be measured using approaches that are sensitive to changes in neural states that might not be reflected in tonic activity. The impulse response approach  borrows Using this approach, it has been possible to observe robust memory signals in the impulse response despite dramatic differences in activity-based decoding between active and latent items . This suThe classic biased-competition model of attention proposed that perceptual templates in WM bias visual processing to prioritize task-relevant items . This idIndeed, there is extensive evidence for such persistent activity associated with WM and preparatory attention. During WM delays, persistent activity occurs across many brain areas , from thA very similar profile of activity is observed for preparatory attention. In preparation for visual search guided by a specific object or location in WM, activity in visual areas representing the relevant object  or locatDespite the general appeal of elevated baseline activity linking WM and attention, the specific neurophysiological evidence is not straightforward. Although classic evidence for item-specific delay activity highlighted pre-activation of target items, the actual correspondence between selectivity during the delay and sensory-related responses is more complex . A neuroA different but related idea is that WM establishes a match filter in sensory areas that effectively computes the perceptual similarity between incoming sensory signals and an internal template . TheoretAlthough the match filter model is typically invoked to explain WM decisions e.g., , the matIn general terms, WM can be thought of as setting the initial conditions for state-dependent processing . The iniMnemonic states could be expressed via elevated patterns of neuronal activity and/or altered patterns of synaptic weights over short and long timescales. In terms of WM specifically, understanding the relative contributions of neural states defined by activity patterns versus activity-silent traces remains an important area for investigation . VariousIn summary, a functional perspective re-casts WM as a flexible shift in how the brain prepares to process future information rather than just maintaining a representation of past information. Considered this way, it is the functionality of the neural state that is most important and not merely the decodability of memory content. Decodability is only a minimal requirement for a memory. To understand how memories are stored for future use , it is necessary to understand how mnemonic states interact with subsequent input to produce appropriate output. Recent methodological developments provide an expanding toolbox for exploring the functional properties of mnemonic states. For example, impulse perturbations provide a powerful tool for probing the functional state during memory delays . AnalysiIn principle, many of the mechanisms we have considered in the context of how working memories guide future processing may also apply to LTM. It will be important for future studies to determine the extent to which activity-silent LTM representations modulate information processing directly, depending on the overlap between present and past settings and goals. It will be informative to understand under what conditions long-term traces are prioritized and energized to guide adaptive behavior. In the latter context, it will also be interesting to learn whether or when activated LTM traces necessarily operate through functionally active WM states to guide attention e.g., .We have considered memory through a different temporal lens. Rather than focusing on how memories echo the past, we have considered how we use past experience to anticipate relevant events to unfold. In addition to providing evidence that traces across several timescales premember events proactively and dynamically, we argue that this basic ecological function of memory shapes the content and the format of what is stored, maintained, and accessed. Significant work lies ahead to understand how mnemonic neural substrates facilitate the processing of incoming information to guide adaptive behavior. Looking at memory from this perspective opens many interesting doors for future exploration, such as the types of memory-based modulatory mechanisms, the existence of a common or multiple memory-based priority maps to guide attention, and how memories can be selective and context dependent and yet be used to generalize to novel situations.


Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiology and extends longevity. We have shown that deficiency in Nrf2 in young Nrf2KO mice leads to an increase in senescent cells, with increased levels of pro-inflammatory cytokines in various tissues, including the brain. Both the cellular senescence and SASP decrease significantly when these mice are treated with rapamycin. Our current work focuses on determining whether cellular senescence contributes to premature AD-like pathogenesis in mouse models of AD. Indeed, it has been shown that Nrf2 deficiency in mouse models for AD leads to exacerbated pathology, suggesting that increased inflammation, due in part to the increased SASP-producing senescent cells, might be contribute to this phenotype. We are testing whether the burden of senescent cells in the brain on mouse models of AD can be reverted by rapamycin.


Multi-sectoral, integrated interventions have long been recommended for addressing mental health and its social determinants  in settings of ongoing adversity. We developed an integrated health and protection intervention to reduce psychological distress and intimate partner violence (IPV), and tested its delivery by lay facilitators in a low-resource refugee setting.n = 60) who received the intervention delivered by trained and supervised lay refugee facilitators. Relevance, feasibility and acceptability of the intervention were evaluated through quantitative and qualitative interviews with participants. We assessed instrument test-retest reliability (n = 24), inter-rater reliability (n = 5 interviews), internal consistency, and construct validity (n = 60).Formative research to develop the intervention consisted of a structured desk review, consultation with experts and local stakeholders , and qualitative interviews . Given existing efforts by humanitarian agencies to prevent gender-based violence in this particular refugee camp, including with  perpetrators, we focused on a complementary effort to develop an integrated intervention with potential to reduce IPV and associated mental health impacts with female IPV survivors. We enrolled Congolese refugee women with elevated psychological distress and past-year histories of IPV , incorporating brief Cognitive Processing Therapy (focused on helping clients obtaining skills to overcome negative thoughts and self-perceptions and gain control over the impact these have on their lives) and Advocacy Counseling . On average, participants attended two-thirds of the sessions. In qualitative interviews, participants recommended adaptations to specific intervention components and provided recommendations regarding coordination, retention, safety concerns and intervention participation incentives. Analysis of the performance of outcome instruments overall revealed acceptable reliability and validity.We found it feasible to develop and implement an integrated, multi-sectoral mental health and IPV intervention in a refugee camp setting. Implementation challenges were identified and may be informative for future implementation and evaluation of multi-sectoral strategies for populations facing ongoing adversity.ISRCTN65771265, June 27, 2016. Refugees may experience a range of adversities, occurring in the period preceding displacement, during displacement, and in the post-migration environment , 2. StreAlthough many individuals display remarkable resilience, a sizeable proportion of refugees experience psychological distress that impairs daily functioning, for example symptoms associated with disorders related to stress, mood, anxiety, and somatoform disorders , 7. WhenSocial adversity and mental health may be linked in vicious cycles. Epidemiologic evidence suggests that challenges in meeting basic needs, protection, livelihoods, and limited access to education and other social services are related to psychological distress in refugee populations and are both risk factors and consequences of mental health concerns –16. IntiThe prevalence of IPV in refugees is high, much higher than rates of sexual violence perpetrated outside of the household , and is Although future research is critical to detail the exact mechanisms, the current literature suggests that symptoms of common mental disorder may confer risk for IPV (re-)victimization. Addressing psychological distress may thus be one of multiple important targets for the reduction of IPV, particularly for women in refugee camps and other low resource settings with sufficient resources for women to protect against re-victimization. There is limited empirical research characterizing the exact mechanism underlying the bidirectional association between mental health and IPV . HypothePrevious efforts to integrate survivor-focused IPV prevention and mental health treatment interventions have primarily been implemented and evaluated in high-income countries and have focused largely on addressing IPV and co-occurring substance use and post-traumatic stress symptoms or have largely focused on PTSD and depression –37. ThesWhen exploring the potential impacts of integrated IPV and mental health interventions, it is imperative to consider other relevant contributors and correlates of IPV at the family-, community- and socio-cultural levels . IntegraGiven that social determinants and mental health are likely interlinked in bi-directional ways, the development of integrated, multi-sectoral interventions that can address both social determinants and mental health at the same time is critical . AlthougWe aimed to develop a multi-sectoral integrated intervention for psychological distress and IPV, meaning that we introduced a program that combined mental health treatment and IPV prevention intervention components  into the protection sector. The multi-sectoral nature of this intervention refers to 1) the inclusion of health priorities, which is usually as seen as outside the scope of protection work, 2) the incorporation of lay personnel trained in both protection and mental health, and 3) coordination with the formal health sector for specific functions such as referral of severe mental health problems and other health concerns. In this paper, we describe formative research aimed at developing a multi-sectoral intervention that integrates a focus on psychological distress and intimate partner violence for refugees in low-resource contexts. More specifically, the objectives of this study were to: (1) conduct formative research to inform the design of a multi-sectoral, integrated survivor-focused mental health treatment and secondary IPV prevention intervention; (2) examine the relevance, acceptability and feasibility of the intervention procedures in a treatment cohort; and (3) prepare and evaluate the outcome assessment tools and research procedures, with Congolese refugee women in Tanzania.This study was conducted in Nyarugusu refugee camp in northwestern Tanzania. At the time the study started, there were over 60,000 Congolese refugees, primarily from the eastern regions of the Democratic Republic of the Congo (DRC) who fled as a result of decades of war . Women aThe study was implemented in four phases: 1) intervention design; (2) training of facilitators; (3) testing the delivery of the intervention using a treatment cohort; and (4) developing and testing the research tools and procedures. An overview of the flow of research activities is provided in Fig.  intervenThe intervention was designed by integrating information on the needs of the target population and the relevance of potential intervention components produced by: (1) a desk review; (2) study site visit; (3) formative qualitative research; and (4) expert consultation. The desk review followed methods recommended for humanitarian settings , 59 and Following the desk review and preliminary site visit, we conducted a rapid qualitative study with local refugees who were working with humanitarian agencies  working on projects relating to mental health and/or gender-based violence in Nyarugusu refugee camp. This formative research included 40 free list and 15 in-depth key informant interviews with refugee incentive workers. The objective was to assess their perspective regarding the most common psychological problems experienced by refugees, which groups were most affected by these problems, and what types of services and supports were available. After the free list interviews were completed, the problems were ranked with regard to frequency and saliency. In the key informant interviews, specific attention was given to the perceived causes, symptoms and appropriate strategies to address the three most salient problems.We formed a team of international and national experts in the fields of refugee mental health and violence protection, to evaluate and select existing evidence-based intervention components based on the results of the desk review, prior systematic reviews , 62, theTo enhance feasibility and sustainability of the intervention, we followed a task-shifting model , 64. In Intervention trainers  delivered 9 days of training to lay facilitators, which combined training in basic counseling skills, review of the intervention manual consisting of elements of Cognitive Processing Therapy and Advocacy counseling, practice-based role plays and feedback, and self-care strategies . Training primarily occurred through brief didactic sessions in English and facilitated by a Swahili translator with clinical experience followed by role-plays to practice delivering the intervention and receive feedback from trainers and peers. This preliminary training  was supplemented by two refresher trainings, which were led by mental health professionals  in Swahili . Supervision of sessions provided to participants enrolled in the treatment cohort (see Phase 3) was conducted by phone and intermittent field visits by a clinical supervisor (TN). The clinical supervisor observed sessions and provided feedback to facilitators through group supervision meetings. Facilitators also discussed challenges they were experiencing during these meetings with the clinical supervisor and solutions were discussed amongst the group. Furthermore, if facilitators identified challenging areas of the intervention manual that were difficult for them to deliver or for participants to understand, these were noted, discussed with the supervisor and brought to study investigators for discussion regarding whether adaptations should be made to the manual. Study investigators encouraged the facilitators to provide potential solutions and recommendations to the challenges they faced in order to inform adaptations to the manual and intervention procedures.To evaluate the implementation of an integrated IPV and mental health intervention, we enrolled a cohort of 60 participants to participate in the intervention. The study sample consisted of adult (18+ years) female Congolese refugees living in Nyarugusu refugee camp who had been in an intimate relationship in the last 12 months and reported past-year physical or sexual IPV and elevated symptoms of psychological distress. We did not place restrictions regarding whether the woman was currently in the relationship and/or living with their most recent partner. Screening of past-year physical or sexual IPV was conducted using the Abuse Assessment Screen (AAS) . Psycholn = 17).All participants provided oral consent for screening and, if eligible, written consent to participate in the baseline interview and Nguvu intervention. The baseline interview was intended to complement the information gathered during screening and included additional measures of demographic characteristics, IPV, functional impairment, trauma history and major life events, social capital, safety planning/behavior, coping strategies and service utilization. All study procedures were reviewed and approved by the Johns Hopkins Institutional Review Board (USA), Muhimbili University of Health and Allied Sciences Institutional Review Board (Tanzania), and the National Institute for Medical Research (Tanzania). Eligible participants who consented to participate and completed the baseline interview were assigned to a Nguvu intervention group. Intervention sessions lasted approximately 2 h each and were scheduled to occur weekly over an eight-week period, which was considered a reasonable duration for this type of intervention in the study setting. After completion of the intervention, a subset of participants representing high attenders  and low attenders  were selected to participate in qualitative semi-structured interviews to examine the relevance and acceptability of the Nguvu intervention . The feasibility of implementation was further examined using attendance as a quantitative indicator of retention. Participant responses to exit interview questions were reviewed by two researchers who participated in the training and implementation of the treatment cohort. Responses to open-ended questions were summarized using thematic analysis.Descriptive statistics of the age, ethnicity, marital status and family composition were calculated to characterize the overall treatment cohort sample , IPV (primary) and functional impairment (secondary). In addition to screening for IPV and mental health problems using the AAS, HSCL-25 and HTQ, the baseline interview included the assessment of IPV using an adapted version of the Conflict Tactics Scale , 73; tran = 60) completed a screening and baseline interview. A subset (n = 24) of eligible participants repeated the screening and baseline interview approximately 1 week after the initial baseline interview in order to examine test-retest reliability. All interviews were conducted by trained research assistants who were also members of the community, most of whom had prior experience in data collection. During interviewer training, inter-rater reliability was evaluated through all interviewers’ observing and independently recording responses from five interviews.All treatment cohort participants (n = 17). Any themes that emerged relating to the research procedures during the coding and thematic analysis process were examined as potential explanations of acceptability, particularly as they related to safety and ethics. Feasibility of the research procedures was assessed using indicators of instrument reliability, which reported on the ability of our measurement tools and methods to consistently assess our primary outcomes across time, items and interviewers. More specifically, test-retest reliability (r) examined the consistency in measurement reported by the same participant (n = 24) in interviews scheduled to take place 1 week apart. Inter-rater reliability  examined consistency in measurement between interviewers observing the same five interviews. Lastly, internal consistency (Cronbach’s α) examined the homogeneity of items within each scale using data from all 60 participants.To assess the relevance of the outcome measures, we evaluated convergent validity using baseline data from all 60 participants included in the treatment cohort. We examined convergent validity between all total and subscale scores for primary and secondary outcomes using Spearman rank order correlations. To assess acceptability of the research procedures we used data from the subset of high and low intervention attenders who participated in the qualitative exit interviews after the intervention had been delivered (Findings from the desk review  and consn = 40) with refugees who had experience working with humanitarian agencies in Nyarugusu reported that the three most salient problems affecting women who had experienced IPV translated to stress , sadness (huzuni) and fear (hofu). Descriptions of these problems provided in the 15 in-depth key informant interviews were broadly consistent with symptoms of common mental disorders   was the only rigorously evaluated psychological intervention tested with adult gender-based violence survivors in the context of armed conflict in a low-resource setting, according to the most recent systematic review at the time of writing . CPT wasTo enhance feasibility in a low-resource, dynamic refugee setting, we selected a 6-session protocol of the CPT intervention , 81 as oWith regard to IPV-focused intervention components, advocacy counseling has shown promising results both to reduce IPV and short-term mental health outcomes . In lineAdvocacy counseling focuses on increasing autonomy, empowerment and strengthening linkages to community services by helping survivors process experiences of IPV and explore potential solutions that are supported by the facilitator through goal setting and safety planning –86. EmpoTo emphasize the psychological and social empowerment goals of both components of the intervention, we refer to it as Nguvu, the Swahili term for strength. The structure of Nguvu, is detailed in Table We found that it was feasible to train lay community members to deliver Nguvu, which was similar to findings from studies that have utilized paraprofessionals or research staff to deliver CPT and advocacy counseling, respectively , 85. Thrn = 7), elevated psychological distress (n = 10), they didn’t report having an intimate partner in the past year (n = 4), or they did not meet either of the past-year IPV or elevated psychological distress criteria (n = 20). On average, participants were 28.6 years old (SD = 10.4), over half were of Bembe ethnicity (59.7%), married (58.3%), and most participants had children . Twenty percent had been selected and begun the process of resettlement to a country other than Tanzania or the DRC at the time of intervention. The majority of eligible participants (86.7%) reported experiencing both physical and sexual violence perpetrated by an intimate partner during the past year on screening measures. Levels of symptoms of post-traumatic stress, depression and anxiety were substantial, with average symptom scores ranging between a “moderate amount” to “a lot” of symptoms during the past 2 weeks, as per the eligibility criteria.Of the 102 participants screened, 61 (59.8%) met eligibility criteria of which 60 consented to participate in the baseline interview and intervention. The 41 ineligible participants were excluded because they did not meet criteria for past-year IPV . As per the intervention protocol, the first session was delivered individually followed by seven group sessions. On average, participants attended 66% of Nguvu sessions, however, with substantial variability by facilitator pair (52–79%). Only two participants did not attend any sessions and approximately half of the participants attended at least 75% of sessions . The highest proportional attendance was observed for session one (92%) with the lowest attendance observed at session six (57%).Seven participants who attended three or fewer sessions and ten participants who attended six or more sessions completed exit interviews after the intervention was complete. Overarching themes of these interviews included perceptions of the intervention, retention issues, safety concerns and suggestions for improving Nguvu. In general, the intervention was thought to be relevant and helpful, particularly discussions about IPV and homework assignments relating to daily practice of the ABCs, thinking questions, changing thoughts, and relaxation skills. The most difficult parts of Nguvu to understand were also the ABCs and changing thoughts. The reasons for absence from sessions included health problems, parenting and childcare, as well as prior engagements , and lack of information due to poor communication. To improve retention the participants suggested that information about session scheduling be provided with more advance notice and also to increase communication between Nguvu staff and participants by providing mobile phones and visiting participants’ homes.We were particularly interested in experiences of safety given the sensitive nature of IPV and the importance of confidentiality to avoid perpetuating or increasing women’s risk for ongoing violence. When asked about safety, all of the seven high attenders reported feeling safe participating in Nguvu, whereas one of eight low-attenders who responded to questions about safety reported not feeling safe at all and two did not provide a response. One participant reported on safety challenges that one of her acquaintances had experienced stating that “because of her husband, she felt like if [the husband] knew it would be a problem and that would complicate the matter even more, considering the husband’s situation”. Participants suggested that improving communication and organization would also improve safety because women would be aware, in advance, of the exact time and date of sessions. Participants did not report concerns about other community members finding out about their participation - safety concerns primarily were related to their partner’s awareness.Participants also provided other recommendations for improving Nguvu prior to implementation of a randomized feasibility trial. These suggestions included involving male partners  and providing services for them, improving communication and organization, providing food and other incentives for attending sessions, increasing the number and continuity of sessions, and incorporating different projects and activities into the intervention.r = 0.31). In general, IPV was most strongly correlated with symptoms of PTSD.Bivariate correlations between primary and secondary outcomes revealed good external construct validity indicated by moderate correlation coefficients, particularly between mental health constructs Table . The psyIn the qualitative exit interviews participants did not mention safety or ethical concerns relating to the research procedures. Furthermore, we did not identify adverse events related to the research procedures during the treatment cohort. We identified specific adaptations to the allocation procedures that were needed to improve acceptability. For example, during supervision the facilitators described that women preferred that the intervention groups be more homogeneous in terms of age composition. More specifically, women reported having elder relatives as members of their intervention group and they were uncomfortable disclosing information about violence occurring within their relationship to these relatives.r = 0.452). Additionally, internal consistency of the functional impairment and psychological IPV items was low . Inspection of the item-rest correlations revealed several items that were weakly correlated with the remaining items and perhaps unrelated to functioning in the sample such as farming, trading and other income-generating activities. Determining which items to remove was based on low item-rest correlations as well as discussion with local staff about the relevance of given items to the concept of functioning among women in Nyarugusu camp. Removal of ten items on the functional impairment measure improved internal consistency to an acceptable level (α = 0.797).Examination of the primary outcome measures revealed overall good test-retest reliability, inter-rater reliability and internal consistency  and others that were not related to the intervention . Lastly, the treatment cohort participants were recruited from a single zone in the refugee camp. It is possible that there are differences between Congolese refugee women by zone, but there may also be implementation challenges that we did not experience, such as transportation and access, that could impact the feasibility of a study extended to women living in all zones in Nyarugusu refugee camp. Another limitation related to generalizability is that the participants represent women who have experienced IPV in the past year, which may exclude women with prior-to-past-year histories of IPV or other related histories of violence.In general we found that it was possible to implement an integrated health and protection intervention to address co-occurring psychological distress and IPV in a complex, dynamic refugee setting. Although feasible, we identified several challenges to implementation specific to the intervention content and delivery, administrative and research procedures, as well as systems-level factors, which may be informative in the design of similar multi-sectoral interventions for populations experiencing multiple adversities. The treatment cohort presented in this article provided insight into some unforeseen challenges that were addressed prior to the conduct of a larger feasibility randomized controlled trial. Forthcoming results from the randomized feasibility trial may provide indication as to whether the modifications improved the relevance, acceptability and feasibility of the intervention as well as whether it may be feasible to evaluate such a program through a large-scale, randomized controlled trial.


We write in response to Lawton et al.’s  important systematic review comparing the outcomes of total ankle replacement (TAR) and ankle arthrodesis (AA) after reviewing the existing literature. Traditionally, AA was the gold standard treatment for ankle osteoarthritis but there is renewed interest in TAR given modern design advantages of preserved ankle motion and gait. We outline some pertinent issues for surgeons to consider when interpreting results from review articles comparing treatment types given the limitations of primary studies. These include significant clinical heterogeneity from the indication for surgery, different treatment type subgroups and from poorly defined clinical outcomes. Letter to the editorWe recently read with interest the article written by Lawton et al.  that wasThe above article highlights apparent and important limitations of current literature including a lack of direct comparative studies, cohorts with long-term follow-up and randomised controlled trials (RCTs). However, there are more subtle considerations which surgeons should consider when interpreting the clinical significance of pooled results from reviews comparing the outcomes of TAR and AA.There is a great deal of clinical heterogeneity from primary studies investigating the outcomes of TAR and AA from multiple sources. From our own literature searches, the indication for surgery is rarely clearly defined and is often phrased as end-stage arthritis. This is a heterogenous definition which may include rheumatoid arthritis, neuropathic arthritis, traumatic osteoarthritis, and primary osteoarthritis. Each of these pathologies has specific but differing risks associated with surgery.Furthermore, the surgical treatments used are often broad with no concise definition. TAR can be divided into subgroups by the implant’s generation and the number of components such as fixed (two-component systems) and mobile bearings TARs (three component systems) . AA procPrimary studies rarely define endpoints of interest including revision, reoperation, non-revision reoperation, and complications which may explain why there is no consensus over which treatment is superior. This is presumably why these endpoints were not clearly defined in Lawton et al.’s review  and realAdditionally, the primary studies included in the analysis vary significantly in follow-up duration and the mean age of patients undergoing surgery. From Lawton et al.’s  review, We have additionally identified other specific limitations to Lawton’s review. It remains unclear why an arbitrary cut off of 200 ankles for TAR and 80 ankles for AA was used as inclusion criteria. Perhaps this arbitrary cut-off was guided from a pilot search, but this potentially introduces a selection bias—with possible inclusion of poorer quality AA studies. It is also interesting that the overall sample size for TAR is 2239 ankles, compared to 608 ankles from AA. Furthermore, studies with lower numbers of ankles for AA were included. This is surprising and counterintuitive, given that AA is regarded as the gold standard, and has been performed more frequently and for longer.We feel that given these points, there should have been a paragraph comprising a risk of bias summary for included studies, to make the quality of primary studies clear and that a summary of patient-reported outcome measures should have been included, given these are important to patients when consenting for surgery.We agree with the authors’ conclusions that given a lack of high-quality direct comparative studies, the decision of which treatment option should be made on a case by case basis. However, we feel that no conclusions can be made from the pooled analysis, and there is little merit reporting this, given the limitations of primary studies in defining endpoints consistently, heterogeneous clinical indications for surgery, and imprecise surgical treatment definitions. Some clarity on which modality is superior for ankle osteoarthritis may be reached from the large multicentre TARVA (TAR versus AA) RCT currently underway . There i


S. pyogenes, that have a remarkable capacity to degrade and disarm IgG. They have shown positive results in several in vivo models of autoimmunity, and treatment with IdeS has successfully been used to inactivate HLA alloantibodies in patients undergoing renal transplantation. Both IdeS and EndoS have the potential to become precision tools to replace plasmapheresis in the treatment of vasculitic emergencies and a clinical trial of IdeS in anti-GBM vasculitis is now ongoing.In primary systemic small vessel vasculitis autoantibodies are common and seem to play an important role in the pathogenesis. Autoantibodies in vasculitis are preferentially directed against components of the immune system or directly against components of the vessel wall. Plasmapheresis is often applied in emergency situationists when the function of vital organs is jeopardized, the level of clinical evidence to apply such therapy, however, varies between low and non-existing. Plasmapheresis is a blunt and unspecific instrument that requires several sessions to achieve a substantial reduction of autoantibody levels. IdeS and EndoS are two relatively recently discovered enzymes produced by  The association of autoantibodies and inflammatory diseases was established more than 60 years ago ; and nowVasculitides are broadly divided into primary and secondary forms, where primary vasculitides are diseases where inflamed blood vessel is the defining and most prominent feature. Primary vasculitides are further divided based on vessel size into large vessel, medium-sized vessel and small vessel vasculitis . Autoantin vitro studies indicate a role for anti-neutrophil cytoplasm antibodies (ANCA) in the pathogenesis of small vessel vasculitides such as microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA)  , 17. Theis (GPA) . The mosis (GPA) . Howeveris (GPA) , 20. IgAis (GPA)  and cryois (GPA)  are immuis (GPA) . Immune is (GPA) . PhysiocStreptococcus pyogenes, one of the most significant bacterial pathogens in humans, has evolved multiple mechanisms to avoid antibody attack and complement activation. IdeS, Immunoglobulin G degrading enzyme of Streptococcus pyogenes, is a secreted cysteine proteinase which cleaves all four human IgG subclasses with a unique degree of specificity; apart from IgG no other substrate has been identified (1)2 fragment the enzyme has to bind to the Fc region, and the remarkable specificity lies in this initial protein-protein interaction 2 fragments can continue to form immune complexes also after losing their Fc tail.IgG class autoantibodies are common in primary small vessel vasculitis and they seem to participate in the pathogenesis. Today plasma exchange is often employed to reduce levels, but this treatment is unselective and rather ineffective. IdeS and EndoS are novel precision tools the rapidly either cleaves or disarms the IgG molecules. Whether this would lead to meaningful clinical responses remains to be determined in each individual disease. Anti-GBM disease, where the pathogenesis seems to be most straight forward, is first in line and a clinical trial is already ongoing.MS wrote the first draft of the manuscript and then both authors contributed on an equal basis.Hansa Biopharma AB owns the commercial rights for IdeS and EndoS as pharmaceuticals, and LB is listed as an inventor on the patents. MS and LB received research grants from Hansa Biopharma AB, and LB has an extensive research contract with the company.


Indy (I’m not dead yet) gene encodes a plasma membrane transporter of Krebs’ cycle intermediates with highest affinity for citrate. Indy is the fly homolog of a mammalian mIndy (SLC13A5), which has the same physiological function. Reduced expression of the Indy gene extends longevity in fruit flies and worms. Genetic and pharmacological INDY reduction affects metabolism in flies, worms, mice, rats and non-human primates by affecting the levels of cytoplasmic citrate. In flies, INDY is predominantly expressed in the midgut, fat body and oenocytes, all tissues with a key role in metabolism. Our first goal was to examine our working hypothesis that INDY reduction in the midgut regulates citrate levels leading to metabolic changes that preserve intestinal stem cell (ISCs) homeostasis and slows aging by modifying Insulin/Insulin-like signaling (IIS). ISC homeostasis is vital for midgut homeostasis and contributes to health and longevity. We found that reduction of Indy preserves ISC homeostasis and intestinal integrity. The IIS is a key nutrient sensing pathway, which regulates growth, metabolism and longevity. Indy reduction is associated with decreased IIS activity. Our second goal was to examine the role of IIS in Indy mediated changes in ISC homeostasis and health. We found that at least some of INDY’s beneficial effects on fly health are mediated by the IIS.


Significant declines in everyday functioning are often indicators of cognitive impairment. Although researchers agree that a diminished ability to carry out a variety of instrumental activities of daily living (IADL) tasks is a harbinger of cognitive impairment (CI), studies have repeatedly found that a compromised ability to successfully complete financial management tasks may be one of the initial IADLs affected by prodromal CI. Due to the combination of compromised financial functioning and the increased prevalence of CI, older adults as group are, therefore, put at a greater risk for financial abuse and exploitation. The aims of this scoping review were two-fold: 1) to synthesize current literature on CI as it relates to financial decision-making (FDM) and 2) to analyze the measures and instruments used to assess FDM in older adults. In a review of four databases, 39 studies were identified that met inclusion criteria. These studies used 22 different instruments to measure and assess financial functioning. Across the 39 studies, consistent themes emerged relevant to factors that impacted cognitive impairment and financial functioning. These themes included participants’ education levels, premorbid financial literacy, and age. White participants were overrepresented in research samples from these studies. Future research should investigate how FDM and early signs of CI may interact in people of color. Additionally, research should be focused on how to make instrumentation more accessible and feasible for the general public to administer without extensive training. This would enable the lay population to more easily identify early signs of cognitive impairment.


Subsequently, myelin  allows for highly complex yet compact circuitry. Cognitive processes such as learning require central nervous system plasticity throughout life, and much research has focused on the role of neuronal, in particular synaptic, plasticity as a means of altering circuit function. An increasing body of evidence suggests that myelin may also play a role in circuit plasticity and that myelin may be an adaptable structure which could be altered to regulate experience and learning. However, the precise dynamics of myelination throughout life remain unclear – does the production of new myelin require the differentiation of new oligodendrocytes, and/or can existing myelin be remodelled dynamically over time? Here we review recent evidence for both  Axons that are fully myelinated along their length conduct impulses many times faster than unmyelinated axons of the same cross sectional size , glial cells called oligodendrocytes extend many processes into their surrounding environment, which concentrically wrap membrane around axons to form myelin sheaths. Myelin sheaths enable the rapid saltatory conduction of action potentials, by localising voltage-gated Nanal size . Therefonal size . Additional size  and neurnal size . Howevernal size . Modificnal size . Subtle Recent evidence suggests that myelin may be adaptable in response to circuit activity. Whole-brain diffusion tensor imaging can be used to measure broad changes in the myelin-rich white matter over time – such experiments in humans and rodents have shown that learning a new task correlates with white matter alterations in relevant brain regions . CellulaHowever, we still do not know whether or how the myelination of circuits is dynamically regulated throughout life. Rodent work indicates that new oligodendrocytes are generated throughout the CNS even in adulthood , and OPCin vivo imaging studies that are beginning to clarify the dynamics of myelination, which will also allow us to begin to understand how such dynamics might impact neural circuit function.To fully understand the precise dynamics of oligodendrogenesis, myelin formation and myelin remodelling throughout various stages of life, longitudinal imaging at high-resolution represents the gold-standard approach. Here we provide an overview of recent in vivo, two recent studies utilised repeated two-photon imaging of the mouse somatosensory cortex over extended periods of time. To begin to definitively address how oligodendrocytes are generated and how myelin is made and dynamically remodelled Similarly, de novo myelination could be modulated by cortical circuit activity throughout life, perhaps to fine-tune the function of those same circuits.Could the generation of new oligodendrocytes (and subsequently new myelin) in the adult cortex be responsive to circuit activity? Previous research has shown that reducing sensory input by removing whiskers from mice leads to reduced oligodendrogenesis in the somatosensory cortex . To inveMany questions remain to be addressed: what is the effect of oligodendrogenesis and new myelination on actual circuit function? Does neuronal activity enhance the long-term survival of myelinating oligodendrocytes? It is possible that the loss of oligodendrocytes in old age is due to age-associated reduction in neuronal activity, which might, in turn, affect overall oligodendrocyte survival. Alternatively, it may be that oligodendrocytes have a limited lifespan independent of neuronal activity . In either case, circuit stimulation could help alleviate age-associated myelin loss by either promoting survival of existing oligodendrocytes or stimulating the production of new oligodendrocytes. This in turn could have significant implications in the treatment and prevention of age-associated cognitive decline.de novo myelination can, in principle, target active axons/circuits. It remains unknown how long-lasting changes to myelin in response to neuronal activity might be. The long-term survival of myelinating cells noted by Activity-mediated oligodendrogenesis is not restricted to the somatosensory cortex – young adult mice undergoing motor learning also show an increase in the number of newly differentiated oligodendrocytes in the motor cortex . What abde novo myelination may occur in many CNS regions, where axons suitable for myelination have sufficient unmyelinated space. However, it remains unclear to what extent oligodendrogenesis continues in different areas of the adult human brain. Carbon-dating analysis suggests that most oligodendrocytes in the corpus callosum tract are generated in early childhood . In addition, even very subtle myelin remodelling could alter the lengths of the nodes themselves. It has recently been shown that node length can vary extensively in the optic nerve and in the cortex, and that changing the node lengths along an axon can, in principle, also significantly alter conduction velocity . WhetherBoth Similar sheath length stability has also been described elsewhere; Why do some sheaths in the cortex change in length, whilst others do not? This may reflect diversity in the demands of distinct neural circuits. Axonal diversity has been observed during initial myelination in the zebrafish spinal cord, where some axons use synaptic vesicle release to regulate myelin sheath number and length while others do not . This raDoes sheath length stability reflect an inability of sheaths to remodel? Experiments in the zebrafish suggest that sheath length remodelling can be induced when the myelination profile of an axon is disrupted. Do stable myelin sheaths in mammals also have this capacity to remodel when the myelination pattern is disrupted? Further longitudinal studies coupled with demyelination are required to answer this question. It is possible that such remodelling is not induced by neuronal activity but is a compensatory mechanism for myelin loss. Age-associated oligodendrocyte loss could trigger remodelling of surviving sheaths to cover denuded portions of axon and therefore help maintain circuit function. Live imaging of myelin sheaths in old age could determine if this is the case.de novo myelination to produce thicker sheaths.The live imaging studies discussed here have all assessed myelin sheath length dynamics, but not myelin sheath thickness. Can sheath thickness be dynamically regulated? Stimulating PI3K/AKT/mTOR signalling in oligodendrocytes of adult mice triggers additional myelin wrapping to increase sheath thickness . This maIt therefore seems that, although myelin sheaths are capable of remodelling when myelin is disrupted, most sheaths are generally stable in length. This stability is potentially due to the maintenance of early established myelination patterns optimised for circuit function.de novo myelination and sheath remodelling in cortical grey matter. Cortical circuits receive and send information via many regions, such as the spinal cord and corpus callosum, and so changes to myelin in several different CNS areas could alter signalling in a single circuit. The CNS is traditionally described by appearance after formaldehyde fixation, where “white matter” describes the heavily myelinated axonal tracts, while “grey matter” describes regions densely packed with neuronal cell bodies, dendrites, and synapses. However, this classification is overly simplistic; OPCs produce myelinating oligodendrocytes in both grey and white matter  occurs even in adulthood, and that this can be enhanced by stimulating circuit activity. Once myelin has formed, it is stable with little turnover of oligodendrocytes and limited remodelling of the lengths of existing myelin sheaths. However, these stable structures may retain the capacity to remodel if myelin is disturbed. This has interesting implications concerning the plasticity of myelin in maintaining circuit function during injury, disease, and old age. Precisely how changes in myelination affect the function of the underlying circuit remains to be seen. Ultimately, a circuit-level approach, integrating analysis of myelin dynamics with direct measurement of circuit function, is required to fully appreciate how dynamic myelination influences overall nervous system function throughout life.The myelination of axons represents a powerful potential mechanism to regulate circuit function throughout life. Research has demonstrated that All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The nature of the tumor antigens that are detectable by T cells remains unclear. In melanoma, T cells were shown to react against major histocompatibility complex (MHC)-associated peptides (MAPs) that are derived from exonic mutations. A recent multi-omic study of hepatocellular carcinomas suggests, however, that mutated exonic MAPs were exceedingly rare, bringing the accuracy of the current methods for antigen identification into question and demonstrating the importance of broadening tumor-antigen discovery efforts. The current enthusiasm for cancer immunotherapy has been fueled in part by major breakthroughs in melanoma. Indeed, melanoma regression can now be achieved through the transfer of in vitro expanded tumor-infiltrating lymphocytes or through immune checkpoint therapy that targets regulatory pathways in T cells. These success stories are explained by two features of melanomas: i) they frequently form bulky and easily accessible tumors from which high numbers of tumor-infiltrating lymphocytes can be harvested, and ii) they are particularly immunogenic because they harbor a very high mutational load. As these approaches become established in the clinic, a key question remains as to the nature of the antigens that are capable of triggering therapeutic T-cell responses.A series of seminal observations propelled interest in exon-derived mutated major histocompatibility complex (MHC)-associated peptides (mMAPs) as potentially crucial to T-cell responses to tumors. The presence of exonic mMAPs on melanoma tumors was demonstrated by mass spectrometry (MS) analyses, and these mMAPs were shown to elicit potent T-cell responses in functional assays. Like other MAPs, mMAPs are short peptides generated by intracellular digestion of proteins. After enzymatic trimming, these peptides bind to intracellular MHC molecules and are then exported at the cell surface. The cardinal feature of mMAPs is that they are coded by genomic regions that bear somatic cancer-specific mutations.The excitement over the discovery of exonic mMAPs has, however, led to widespread acceptance of a speculative concept and to the introduction of a semantic bias. The unproven concept is that the repertoire of exonic mMAPs can be predicted  by combining exome sequencing and algorithms that predict MHC binding. The semantic reductionist bias was introduced when the term tumor-specific antigens (TSAs), also commonly referred to as neoantigens, was used to designate exonic mMAPs, implicitly suggesting that all TSAs were also exonic mMAPs. Formally, however, the terms TSA and neoantigen must encompass not only exonic mMAPs but rather all MAPs that are present only on cancer cells, irrespective of their genomic origin (exonic or not) and mutational status. This is not a trivial issue because exons represent only 2% of the genome, whereas 75% of the genome can be transcribed and potentially translated. Indeed, MS analyses identified MAPs derived from introns, 5′ UTRs, 3′ UTRs, long non-coding RNAs and intergenic regions . Most ofGenome Medicine, Löffler and colleagues report on an important study of 16 primary human hepatocellular carcinomas. They performed exome and transcriptome sequencing and high-throughput shotgun MS analyses of the proteome and MAP repertoire, complemented by highly sensitive targeted MS analyses of selected MAPs [In this issue of ted MAPs . Using tted MAPs . The rested MAPs , they cated MAPs . Second,ted MAPs . Over thted MAPs , as wellHow can we reconcile the scarcity of exonic mMAPs with the compelling evidence that many non-melanoma tumors display immunogenic MAPs? Arguably, the most parsimonious explanation is that the MAP repertoire of cancer cells contains a substantial amount of ‘dark matter’ (antigens that are not detected by the current approaches). In line with this, a recent study found that most TSAs present in human acute lymphoblastic leukemias and lung cancers derive from unmutated non-exonic sequences that are located in introns, intergenic regions and other noncanonical reading frames . These aThe study by Löffler and colleagues shows that MS is the most robust method for high-throughput analyses of the MAP repertoire of tumor cells . NotablyRapid progress in the field and the lack of a standardized nomenclature has led to some confusion in the classification of tumor antigens. We therefore offer a simple classification of tumor antigens based on three criteria: tissue-expression profile, genomic origin and mutational status Table . Tumor-aCGAs are coded by canonical exons that are normally expressed only by germ cells, and their aberrant expression in cancer cells is mostly driven by epigenetic alterations. However, some CGAs are expressed by adult mTECs . AccordiA deep exploration of the immunopeptidomic dark matter will be necessary before conclusions can be reached. Substantial attention should be paid to three features of tumor antigens that will influence their potential for therapeutic translation: the proportion of tumors on which they are present, their abundance on tumor cells and their immunogenicity. Ultimately, clinical studies will determine what is the best way to target tumor antigens. The fact that multiple antigens can be incorporated into a single vaccine makes this approach very attractive. On the other hand, therapies that are based in T-cell receptors (using the injection of cells or bispecific biologics) would make it possible to launch potent attacks on tumor cells, even when the patient is immunodeficient.