Overviews of reviews of healthcare interventions (overviews) integrate information from multiple systematic reviews (SRs) to provide a single synthesis of relevant evidence for decision-making. Overviews may identify multiple SRs that examine the same intervention for the same condition and include some, but not all, of the same primary studies. Different researchers use different approaches to manage these “overlapping SRs,” but each approach has advantages and disadvantages. This study aimed to develop an evidence-based decision tool to help researchers make informed inclusion decisions when conducting overviews of healthcare interventions.We used a two-stage process to develop the decision tool. First, we conducted a multiple case study to obtain empirical evidence upon which the tool is based. We systematically conducted seven overviews five times each, making five different decisions about which SRs to include in the overviews, for a total of 35 overviews; we then examined the impact of the five inclusion decisions on the overviews’ comprehensiveness and challenges, within and across the seven overview cases. Second, we used a structured, iterative process to transform the evidence obtained from the multiple case study into an empirically based decision tool with accompanying descriptive text.The resulting decision tool contains four questions: (1) Do Cochrane SRs likely examine all relevant intervention comparisons and available data? (2) Do the Cochrane SRs overlap? (3) Do the non-Cochrane SRs overlap? (4) Are researchers prepared and able to avoid double-counting outcome data from overlapping SRs, by ensuring that each primary study’s outcome data are extracted from overlapping SRs only once? Guidance is provided to help researchers answer each question, and empirical evidence is provided regarding the advantages, disadvantages, and potential trade-offs of the different inclusion decisions.This evidence-based decision tool is designed to provide researchers with the knowledge and means to make informed inclusion decisions in overviews. The tool can provide practical guidance and support for overview authors by helping them consider questions that could affect the comprehensiveness and complexity of their overviews. We hope this tool will be a useful resource for researchers conducting overviews, and we welcome discussion, testing, and refinement of the proposed tool. Overviews of reviews of healthcare interventions integrate information from multiple similar systematic reviews (SRs) to provide a single synthesis of relevant evidence for healthcare decision-making . As the Different researchers use different approaches to manage overlapping SRs in overviews , 4. SomeIn a companion paper by Pollock et al., we examined the impact of the above inclusion decisions on the comprehensiveness and results of overviews, and we documented the challenges associated with these different inclusion decisions . We founWe used a two-stage process to develop the decision tool. First, we conducted a multiple case study to obtain the empirical evidence upon which the tool is based. We systematically conducted seven overviews five times each, making five different decisions about which SRs to include in the overviews, for a total of 35 overviews. We then examined the impact of the inclusion decisions on the overviews’ comprehensiveness, results, and challenges, both within and across the seven overview cases . Second,To develop the decision tool, we first conducted a multiple case study . Each “cfull inclusion scenario, all eligible outcome data were extracted from all eligible SRs; accuracy of effect estimates was ensured by extracting each primary study’s outcome data only once, regardless of how many SRs contained that study’s data. For the first restricted scenario, all eligible outcome data were extracted from only the Cochrane SRs. For the last three restricted scenarios, all eligible outcome data were extracted from all non-overlapping SRs, and for groups of overlapping intervention comparisons within SRs, outcome data were extracted from the following: Cochrane SR (if available), most recent SR (by publication date or search date), or highest quality SR . Data eTAR tool . For eacTAR tool , 20, 21.full inclusion scenario. We then systematically compared the full inclusion scenario with each of the four restricted inclusion scenarios by documenting the number and percentage of SRs, intervention comparisons, primary studies, and subjects that were lost in each restricted scenario and the number and percentage of outcomes that were lost or changed  in each restricted scenario. We then identified and narratively described groups of similar and contrasting overviews [For each overview topic, we described the characteristics of the verviews , 22 and verviews .We used a structured and iterative process to transform the results of the multiple case study into an evidence-based decision tool, with accompanying descriptive text, to help researchers make inclusion decisions in overviews. We developed the tool using established principles for designing and populating network displays. This involved reconfiguring the inclusion decisions and study results into an ordered decision model with accompanying descriptive text .In the multiple case study, we found that certain variables differentially affected the comprehensiveness and results of overviews . When crThe decision tool was developed iteratively by the same team of researchers who conducted the multiple case study. Thus, all researchers had content and methodological expertise and were familiar with the multiple case study findings. One researcher developed, refined, and finalized the decision tool and its accompanying descriptive text using the above-described process (MP). The additional four researchers oversaw this process and provided several rounds of feedback on the content, placement, and wording of the decision points and pathways in the decision tool, and the content and wording of the descriptive text . All researchers approved the final version of the tool and agreed that it comprehensively reflected the results of the multiple case study. Taken together, the decision tool and its accompanying text can provide overview authors with both the knowledge and the means to make informed inclusion decisions that are specific to the context of their unique overview.The seven overviews included in the multiple case study contained 6–19 SRs (range 0–7 Cochrane SRs and 2–13 non-Cochrane SRs). Tables The above-described results were used to develop an evidence-based decision tool, with empirically derived accompanying text, to provide practical guidance for researchers making inclusion decisions in overviews. The decision tool is presented in Fig. If yes, researchers may choose to include only Cochrane SRs in the overview. An advantage  of this inclusion decision is that researchers are likely (but not guaranteed) to avoid issues related to overlapping SRs (described below in decision point 4). A disadvantage  is that there will likely  be some data loss from non-Cochrane SRs for overlapping intervention comparisons; however, it is unclear whether these additional data are of clinical importance, since some data may come from primary studies in non-Cochrane SRs that were identified by, but excluded from, the Cochrane SRs, for being outside their scope or having methodological deficiencies. Input from clinical experts and other stakeholders may be required to assess whether the Cochrane SRs comprehensively examine all relevant intervention comparisons and available data. Cochrane SRs may be deemed not comprehensive if they do not examine all relevant intervention comparisons or contain all available primary studies . Researchers who are not comfortable answering this question based on the Cochrane SRs alone may opt to search for and identify non-Cochrane SRs  and re-aIf researchers suspect that the Cochrane SRs are not comprehensive, the next decision point asks them to search for and identify non-Cochrane SRs and determine whether the primary studies contained within the included SRs overlap. Researchers may wish to examine the primary study overlap separately for each set of intervention comparisons, as SRs often contain multiple comparisons. If, across all intervention comparisons, the Cochrane and non-Cochrane SRs do not overlap, and the non-Cochrane SRs do not overlap with each other, researchers can include all Cochrane and non-Cochrane SRs in the overview without concern for issues related to double-counting outcome data. This situation was not observed in the current methods study and is likely to be rare. If researchers are unsure whether or to what extent the SRs overlap, they can assess overlap by producing a citation matrix and using it to calculate the corrected covered area .When the included SRs overlap, researchers may opt to include all Cochrane and non-Cochrane SRs if they are prepared and able to avoid challenges related to including overlapping SRs and extracting and analyzing their outcome data. An advantage of this inclusion decision is that it is the only way to ensure that all data from all SRs are included in the overview. A disadvantage is that researchers are likely to encounter multiple challenges when including overlapping SRs in overviews. As described above (decision point 1), primary studies contained within non-Cochrane SRs may have been identified by (but excluded from) the Cochrane SRs for reasons related to eligibility criteria or methodological quality, making it difficult to determine whether and which data from non-Cochrane SRs are clinically relevant. When extracting outcome data, overlapping SRs may analyze and present the same or similar outcome data in different ways and may have discordant results for the same outcome. Further, overlapping, non-Cochrane SRs may be older and of lower quality and may have deficiencies in their conduct and reporting that makes data extraction difficult. All of these challenges may make it difficult for researchers to extract outcome data from overlapping SRs in a systematic and transparent way and may also increase the complexity of other stages of the overview process.If researchers cannot avoid double-counting outcome data from overlapping SRs, they may opt to balance comprehensiveness and complexity by including all non-overlapping SRs; for groups of overlapping SRs, they may opt to include the Cochrane, most recent, or highest quality SR. Using specific criteria to prioritize SR inclusion when confronted with multiple, overlapping SRs can allow researchers to capitalize on the advantages of the previous two inclusion scenarios by avoiding potential issues related to double-counting outcome data while maximizing the amount of data included in the overview. For groups of overlapping SRs, including Cochrane SRs compared to the most recent or highest quality SRs may most effectively minimize both data loss and methodological issues. Researchers may face the following challenges if including the most recent or highest quality SRs for groups of overlapping SRs: recency of SRs may be assessed and operationalized in different ways, some SRs may be “tied” for most recent or highest quality, and conducting quality assessments for the purpose of selecting eligible SRs may be challenging and time-intensive. However, if including the Cochrane SRs for groups of overlapping SRs, researchers should be aware that multiple Cochrane SRs may contribute outcome data to the same comparison , and not all groups of overlapping SRs may include a Cochrane SR.In a multiple case study of seven overviews conducted using five different inclusion decisions, we found that different inclusion decisions differentially affected the comprehensiveness and results of overviews and were associated with different types of challenges . We usedThere are practical considerations involved when using the decision tool in overviews. Specifically, four conditions should be met prior to its use. First, the overview should examine multiple interventions for preventing or treating a health condition, though further testing and real-life application of the tool will help determine whether it can be used with other types of overviews . Second,This decision tool can provide practical guidance and support for overview authors by helping them make transparent and informed inclusion decisions when faced with overlapping SRs in overviews. As the number of overlapping (and possibly conflicting) SRs continues to increase , issues The inclusion decisions presented in the decision tool and examined in the companion paper by Pollock et al.  are descDifferent researchers currently make different inclusion decisions in overviews, but may not understand the ways in which these inclusion decisions affect the comprehensiveness and complexity of their overviews. This study used empirical findings to develop an evidence-based decision tool to help researchers make transparent and informed inclusion decisions in overviews. The tool can provide practical guidance and support for overview authors in two ways: by helping them consider questions that can affect the comprehensiveness and complexity of their overviews and by helping them assess the potential impact, advantages, disadvantages, and trade-offs of the different inclusion decisions. The tool may be useful when developing overview protocols and/or when conducting and reporting overviews. This tool would benefit from additional discussion, testing, and refinement. It may also have relevance to other knowledge synthesis products that include SRs.


Obstructive Sleep Apnoea (OSA) is a common sleep disorder that is associated with daytime symptoms and a range of comorbidity and mortality. Continuous Positive Airway Pressure (CPAP) therapy is highly efficacious at preventing OSA when in use and has long been the standard treatment for newly diagnosed patients. However, CPAP therapy has well recognised limitations in real world effectiveness due to issues with patient acceptance and suboptimal usage. There is a clear need to enhance OSA treatment strategies and options. Although there are a range of alternative treatments , generally there are individual differences in efficacy and often OSA will not be completely eliminated. There is increasing recognition that OSA is a heterogeneous disorder in terms of risk factors, clinical presentation, pathophysiology and comorbidity. Better characterisation of OSA heterogeneity will enable tailored approaches to therapy to ensure treatment effectiveness. Tools to elucidate individual anatomical and pathophysiological phenotypes in clinical practice are receiving attention. Additionally, recognising patient preferences, treatment enhancement strategies and broader assessment of treatment effectiveness are part of tailoring therapy at the individual level. This review provides a narrative of current treatment approaches and limitations and the future potential for individual tailoring to enhance treatment effectiveness. Obstructive Sleep Apnoea (OSA) is a common sleep disorder, characterised by repetitive obstruction of the pharyngeal airway during sleep which leads to intra-thoracic pressure swings, sleep fragmentation, and intermittent hypoxia. These cyclical perturbations provide a mechanistic framework for the association of OSA with a range of clinical morbidity including metabolic and cardiovascular disease, cognitive impairment, cancer and increased rates of mortality –4. PrevaPersonalisation of treatment is particularly important in OSA. As a chronic condition, effective therapy is required over the long-term to promote good health and wellbeing. This requires a therapy that is accepted by the patient, effectively controls the disorder, and is adequately adhered to. The standard of therapy has long been Continuous Positive Airway Pressure (CPAP) devices. CPAP can be viewed as a ‘one size fits all’ solution to OSA, as when applied CPAP prevents OSA regardless of the underlying mechanisms of apnoea and site of pharyngeal collapse, or patient phenotype. There are different pathways to OSA with both structural and physiological risk factors that differ in relative importance between individuals. Structural risk factors include craniofacial structure, enlarged upper airway soft tissues and obesity. Physiological risk factors such as ventilatory control system abnormalities or ineffectiveness of dilator muscle output can also contribute to OSA. Individuals with OSA have their own unique combination of pathophysiological mechanisms that contribute to disease. Knowledge of these provides a means to tailor therapy to an individual.Since its first report in 1981 , CPAP thThe diagnosis of clinically significant OSA is established by the combination of clinical assessment and a diagnostic sleep study, the latter most often an in-laboratory polysomnogram (PSG) or a home sleep study. This should be followed by a discussion between practitioner and patient (and often patients’ partner) that focuses on the individual’s risk factor(s) for the occurrence of OSA and to the presence of significant co-morbidities that may be exacerbated by OSA. Such potentially modifiable risk factors include obesity, nasal and other upper airway pathology, and aggravating lifestyle issues such as smoking and excessive alcohol use. These factors need to be addressed in parallel with direct therapy, used to abolish the pathophysiological events of OSA.Good evidence has accumulated that effective CPAP improves the neurobehavioral and cardiovascular consequences of OSA , 13. StuImportantly, not all patients with OSA accept or are able to tolerate CPAP. Even amongst sleepy patients with moderate -severe OSA adherence to prescribed therapy (defined as > 4 h average nightly use) is poor with only 46–83% being adherent . A numbeThere is an ongoing need to consider alternative therapeutic options. Most current alternative therapy strategies have a common theme in that they are not completely efficacious in all OSA patients. Therefore, a comprehensive understanding of the individual patient phenotype is needed in order to select the most appropriate therapy and to maximise clinical benefit.Obesity is the strongest reversible risk factor for developing OSA. Large epidemiological studies have shown a strong relationship between weight gain and developing OSA –21. Up tDespite this, weight loss leads to significant sleep related symptomatic improvements that may be independent of AHI changes . Weight Positional therapy aims to prevent sleep in the supine position in which sleep-disordered breathing is often more severe. There are a number of devices designed for this purpose, ranging from a tennis ball affixed to the back of a pyjama top to new generation electronic devices, which utilise increasing vibrations from sensors placed on the back of the neck or chest to prompt a move away from the supine body position. Studies of positional therapy from tennis balls to commercial devices have generally shown improvement in AHI but studies are limited to small RCTs and case series . MinimalThe phenotype of OSA patient suited to positional therapy is clearly one for whom apnoeas and hypopneas occur primarily in the supine sleep position, whereas other positions are less affected. Position OSA (P-OSA) is reported in the range of 50–60% of patients undergoing PSG in sleep clinics, with supine-isolated OSA present in 25–30% . Therefom) [m are dental devices, which attach to the upper and lower dental arches in a configuration to protrude the lower jaw relative to the upper jaw. OAm exist in numerous designs which vary in the amount of customisation to the dentition, fabrication material, amount of occlusal coverage, whether the device consists of a single plate (monobloc) or two separate plates, the amount of vertical mouth opening permitted, the advancement mechanism and ability to adjust advancement level (titration). There are limited studies directly comparing different OAm designs but guidelines recommend a customised and titratable device as best practice [m significantly reduce sleep disordered breathing metrics and snoring compared to placebo oral devices (which provide no mandibular advancement) [m reduce AHI by an average of around 50% [Oral appliance therapy aims to reposition craniofacial or intraoral structures in order to increase the pharyngeal airway space and prevent pharyngeal collapse. Oral appliances include tongue retaining devices which aim to hold the tongue in a more anterior position . Howeverm) . OAm arepractice . OAm signcement) –48. OAm ound 50% , and 30–m therapy. These include less severe OSA (lower AHI), less obesity  and younger age. However, these characteristics represent a guide only, and there are no accurate thresholds for any of these factors to exclude patients from therapy [m therapy. Most studies investigating craniofacial structures associated with treatment responsiveness have used lateral cephalometric x-rays, a two-dimensional analysis of the facial profile. There are commonly reported characteristics associated with treatment response including mandibular plane angle, hyoid position, size of upper airway soft tissue and cranial base angle [There are a number of patient characteristics which have been associated with a favourable outcome of OA therapy . Craniofse angle . Howeverse angle . Therefose angle .m therapy, which have varying degrees of clinical applicability, predictive accuracy and validation [m is a clinical barrier.Many prediction methods have been proposed to select patients for OAlidation . For a rlidation . Most stlidation , 55. Othlidation  or drug-lidation  and showsoft tissues  or increase the size of the bony enclosure (eg maxillomandibular surgery), repositioning of the hyoid bone (hyoid repositioning), or increasing nasal patency (eg turbinate reduction surgery) [Upper airway surgery aims to improve anatomy to prevent pharyngeal collapse. Upper airway anatomical impairment can be modelled as an imbalance between the soft tissues enclosed within the maxillo-mandibular bony enclosure . Upper asurgery) .In children, adeno-tonsillectomy is accepted as first line therapy for OSA. In adults, surgery for OSA previously involved a single procedure such as uvulopalatopharyngolasty (UPPP), which reduces upper airway collapsibility . Modern Meta-analysis of trials of maxillo-mandibular surgery also concluded that there were improvements in sleepiness symptoms, and OSA severity in subjects who had failed other therapies including upper airway surgery . MaxilloSelecting the right patient for various upper airway surgical procedures is complex. An initial step may be to determine that their OSA relates largely to anatomical pathophysiology . KnowledSurgery can also target effectiveness of upper airway dilator muscles through Hypoglossal nerve stimulation (HGNS). HGNS is a relatively new approach to treat upper airway collapse that surgically implants a cuff around the hypoglossal nerve attached to an electrical pulse generator in the chest. These devices stimulate the hypoglossal nerve resulting in protrusion of the tongue during respiration. Current devices have a sensor for respiratory efforts and stimulate the hypoglossal nerve to increase tongue protrusion in time with inspiration , 68. In Studies designed to delineate the various contributors to recurrent upper airway closure during sleep identify anatomy, muscle responsiveness, arousal threshold, or respiratory system control as important , 73. A cA low arousal threshold, or propensity to wake easily in response to a disturbance is thought to be important in perpetuating repetitive obstructive events in subjects with OSA by promoting instability around the sleep/wake state , 73. To Pharmaceutical approaches to increasing upper airway activity have also been trialled. Desipramine, an agent which stimulates the noradrenergic neurons can increase muscle response, and reduce upper airway collapsibility , 80, altApproaches aimed at manipulating respiratory control have also been trialled as treatment for OSA. The aim of this therapy is to alter the “Loop Gain” of the respiratory control system. Loop gain quantifies respiratory system response to a perturbation, with a loop gain greater than 1 indicating the response is greater than the disturbance, leading to a perpetuation of the disturbance. A meta-analysis of oxygen therapy in OSA concluded that oxygen therapy improves oxygen saturation and reduces AHI in subjects with OSA, but may also result in the prolongation of apnoeic events . MeasureUnderstanding of the contribution of anatomical impairment and individual non-anatomical contributors to OSA pathophysiology upper airway muscle responsiveness, arousal threshold, or respiratory control in individual patients could suggest success with these emerging treatment modalities, either singularly or in combination.Considerable effort has gone into the development of strategies to enhance CPAP adherence, a critical goal for the attainment of health benefits. These include patient and devices factors. Early follow up by phone and direct clinic attendance enable confirmation of effective treatment use and trouble-shooting of any ongoing or evolving difficulties, and has been demonstrated to augment compliance. Cognitive behaviour therapy has been demonstrated to enhance self-efficacy and the adoption and adherence to CPAP. There is considerable scope to develop personalised approaches to the implementation of CPAP based on patient anatomical and psychological characteristics. For example, personalisation of mask fitting and addressing psychological barriers to treatment or to comorbid insomnia are feasible strategies depending on the patient phenotype.The advent of automatic CPAP improved the efficiency with which CPAP could be implemented, with greater convenience for the patient by enabling implementation in the home setting. Such devices deliver appropriate but varying positive pressure breath-to-breath, and today most CPAP devices have electronic data storage cards that collect important adherence and efficacy data. The superiority of automatic CPAP over fixed-pressure CPAP is not yet proven, although they tend to provide greater convenience. More recently, cloud based technologies have led to the development of patient engagement tools that appear to be associated with better adherence . There aThere are also emerging “big data” opportunities in OSA, particularly through the advent of large-scale cloud based collection of CPAP adherence data. It is envisaged that this will make it possible to define adherence phenotypes, and ultimately using data analytics to identify predictors of treatment adherence. In this way we will be able to tailor interventions to optimise CPAP adherence.We are approaching an era where understanding patient phenotype will allow personalised strategies towards treatment. There is a recent move towards identifying novel phenotypes of patients using discovery or unsupervised machine learning analyses. These methods aim to describe hidden structure within data. An example of unsupervised machine learning is cluster analysis or clustering. Cluster analysis aims to group cases such that cases within the same group (or cluster) are most similar to each other than those in other groups. Clustering methodologies have recently been used to identify novel subtypes of OSA patients based on clinical characteristics. There is emerging evidence that phenotypes identified in this manner may have clinical meaning and ultimately may help to tailor therapy.N = 822, moderate-severe OSA patients) [Clustering methods were applied to data from a self-reported symptom questionnaire in the Icelandic Sleep Apnea Cohort   to eluciatients) . Resultsatients) , althougThese clinical symptom subtypes have now been explored in relation to treatment outcomes in the ISAC cohort . PatientData driven discovery approaches have also been applied to clinical sleep study data  and assoOther discovery approaches include universal assessment of what is going on at the level of the genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics). ‘OMICS’ approaches to characterise molecular signatures associated with OSA are of interest to develop diagnostic markers of disease but could also be used to ascertain disease risk and treatment responses .Anatomical phenotyping of craniofacial skeletal and soft tissue structures related to OSA have been performed by both two-dimensional  and three-dimensional  imaging techniques . Anatomim response. Mallampati score may also be an indicator of the site of pharyngeal collapse, particularly retrolingual collapse [These detailed imaging and simulation processes are complex and are currently beyond the scope of clinical practice for matching individual patients to particular therapies. Another approach is anatomical phenotyping using high-throughput and less expensive methods. For example, it has been proposed that a simple anatomical assessment in the Mallampati Score may be a reflection of anatomical balance  and thiscollapse . A simplcollapse –103. Surcollapse , 105 thecollapse . A quantcollapse .OSA is diagnosed by PSG. In the laboratory a full complement of signals includes airflow, oximetry, respiratory effort, ECG, EEG, EOG, EMG, and body position. In clinical practice this information is for the most part distilled into a single metric, the Apnoea-Hypopnoea Index, on which treatment decisions are currently largely based, although this number is not informative of treatment responsiveness. However, new approaches are emerging to be able to process these signals to derive meaningful physiological information which could guide therapy selection.There is a growing body of algorithms emerging to ascertain pathophysiological contributors to sleep-disordered breathing from clinical sleep signals which have been validated against physiological measurements during research sleep studies. Metrics about contributing pathophysiology to OSA have derived from breathing signals for ventilatory control stability , the levA marker of site of pharyngeal collapse has been identified from the nasal flow signal from sleep studies with simultaneous observation using an endoscope . The perAdditionally other measures may inform the functional outcomes of therapy. The EEG signals from PSG have also begun to be scrutinised to derive novel and potentially prognostic metrics. For example, a continuous measure of sleep depth (odds product ratio) has been derived  with impThe definition of a biomarker is a “biological molecule found in blood, other body fluids, or tissues that is a sign of normal or abnormal process, condition or disease” . Since OFor a long time treatment success has been defined by the measurement of AHI while the treatment is in use. However, this does not take into consideration the time spent off treatment. This is particularly relevant given the low levels of CPAP usage in the real world, and that often it is removed after only a few hours. This pattern of early removal is particularly concerning given recent associations with OSA in REM and cardiovascular morbidity given that REM sleep is more concentrated towards the later half of the night . AlternaAs our understanding of the pathophysiology of OSA expands and underpins the development of personalisation strategies, there is a critical need to develop improved models of healthcare delivery that can support the incorporation of this new knowledge into routine clinical care, thereby improving access to care and patient outcomes. Given the high prevalence of OSA there is a need to build capacity in the system, and there is growing evidence supporting the use of simplified models of care involving primary care physicians or nurse practitioners who are supported by access to specialist sleep services when required , 131. ThThe field of sleep medicine is moving into the era of personalised medicine. This means increasing recognition of the limitations of the previous ‘one-size-fits-all’ approaches to treatment and management of OSA. A key part of this is tailoring therapies to the individual. Although CPAP clearly has a place as a highly efficacious treatment, there are new opportunities to tailor therapies to the individual patient. There is a range of current and emerging treatment alternatives to CPAP, however these generally will not be universally efficacious in all OSA patients. This creates the need to match patients to treatments appropriate to their individual pathophysiology in order to maximise treatment response. Tools for elucidating pathophysiological mechanisms and anatomical phenotypes which are amenable to the clinic setting are evolving rapidly and will help provide tailored treatment pathways. Discovery approaches, applied at clinical, electrophysiological, and molecular levels, could bring in a new era of recognisable clinical phenotypes. Future treatment pathways may, therefore, include the ability to determine which OSA patients are susceptible to comorbidity. Furthermore, which individuals will respond to OSA treatment alone vs. those requiring multifaceted treatment strategies, which will require multidisciplinary models of care. Additionally, the framework for understanding treatment response needs to move beyond just a focus on how AHI improves while treatment is in use. Patient engagement and enhancement strategies are needed regardless of which treatment is implemented, and patient participation in these choices are key for optimising real word treatment effectiveness.


Compulsive Sexual Behaviors (CSB) are a reason to seek treatment. Given this reality, the number of studies on CSB has increased substantially in the last decade and the World Health Organization (WHO) included CSB in its proposal for the upcoming ICD-11. Sixty percent of the neuroimaging studies on CSB published since 2014 aimed to examine similarities and differences between brain mechanisms underlying CSB, gambling disorder, and substance use disorders. One of the crucial brain circuits involved in addiction is the reward system involving the ventral striatum (including nucleus accumbens). There are two distinct theories describing ventral striatal activity in addictions: Incentive Salience Theory (IST) and Reward Deficiency Syndrome (RDS). IST describes increased ventral striatal activations during the anticipation of addiction-related reward, while RDS describes decreased ventral striatal reactivity both during the anticipation of the reward and during the reward processing. Here, we aim to investigate how the findings on ventral striatal reactivity in CSB support each of these two addiction frameworks. For this purpose, we conducted a systematic review of neuroimaging studies on CSB available in Pubmed, EBSCO, and Google Scholar between 2005 and 2018. We found nine relevant research papers. Only four of these studies directly investigated processing of erotic cues and/or rewards and reported findings related to ventral striatum activations. Three of these studies indicate increased ventral striatal reactivity for erotic stimuli, which is consistent with IST and does not support predictions based on RDS. Therefore, the current state of this data suggest that CSB is related to increased ventral striatal reactivity during the anticipation of erotic stimuli. Compulsive Sexual Behaviors (CSB) are a reason to seek treatment for both males –3 and feExcessive time spent on sexual fantasies, urges, or behaviors repeatedly interferes with other important  goals, activities, and obligations, i.e., pornography viewing has become a central interest in one's life, so that family duties or work obligations are neglected;The subject engages repeatedly in these sexual activities in response to dysphoric emotional states, i.e., sexual activity has become a rigid strategy of mood regulation;And/or in response to stressful situations; e.g., during stressful events at work;Despite repeated attempts, the subject fails to control or significantly reduce these sexual activities, i.e., the subject makes numerous unsuccessful attempts to limit problematic activities, but invariably loses control over them after a couple of days;The subject continues these sexual activities despite the risk of physical or emotional harm to self or to others, i.e., engaging in frequent sexual behavior despite serious consequences for relationships  or threat of job loss.The number of studies on CSB has increased substantially during the last decade , 10 and The frequency and intensity of these sexual activities lead to clinically significant personal distress or dysfunction in important aspects of life and do not result from exogenous substance use , bipolar disorder, or paraphilia.One of the crucial brain circuits involved in addiction is the reward system connecting such brain structures as the ventral tegmental area  with the ventral striatum, mesocortical pathways, and cerebral cortex, especially the orbitofrontal and mediofrontal cortex –16. AnatThe ventral striatum receives cortical input from the orbital frontal cortex and anterior cingulate cortex in addition to dopaminergic input from the midbrain. The same region projects output to the ventral pallidum and to the ventral tegmental area, which project output back to the prefrontal cortex through the medial dorsal nucleus of the thalamus. This circuit is an integral part of the cortico-basal ganglia system . DiffereOf the many addiction theories which are of interest, here, we would like to focus on two which allow for very clear predictions about ventral striatal activation and its link to addictive behaviors: Incentive Salience Theory IST, –28] and  and 28)]experienced value of the reward, usually carried by an unconditional stimuli such as heroine consumption; on the other hand, “wanting” is related to the expected value of the reward, often carried by a conditional stimuli . Studies on substance and gambling addiction show that learned conditional stimuli  related to addiction evoke increased responses in the ventral striatum as well as increased motivated behavior (manifested with shorter reaction times) among addicted individuals, while responses to the reward itself remain unchanged or undergo blunting over time . For these specific cues, this group's ventral striatum can be more activated than when compared to the general population and when compared to different types of cues. With this prediction, we aim to review available neuroimaging data on ventral striatal activations in CSB.If CSB is more related only to IST, then we should find more studies showing increased ventral striatal activations during expectation for erotic stimuli among individuals with CSB as compared to healthy controls. If CSB is more related to the RDS, then we should see more studies which demonstrate decreased ventral striatal reactivity for any type of rewards among CSB subjects when compared to healthy controls, and possibly decreased reactivity of the ventral striatum during the expectation of the reward, as well.For the purpose of this review, we searched Google Scholar, Pubmed, and EBSCO databases for scientific papers published in peer-reviewed journals (excluding conference abstracts) between January 1, 2005 and February 22, 2018. We only included publications which utilized functional magnetic resonance imaging (fMRI), as we are interested in the BOLD response of the ventral striatum and included keywords such as compulsive sexual behavior, pornography, sex addiction, hypersexuality, hypersexual disorder, problematic pornography use, and internet pornography addiction. The search was performed on February 22 and February 25, 2018. We only included articles published in English. We have found nine publications which met our search criteria Table –42. InclFirst, we will discuss studies directly addressing cue and reward processing. Among the seven studies reporting ventral striatal activations for erotic cues or rewards, two were conducted on a sub-clinical population [frequent pornography users; , 39 not Taking into account the very limited body of experimental publications (seven) reporting activations of ventral striatum during processing of erotic and non-erotic stimuli in populations meeting the criteria of CSB or in sub-clinical populations, deriving any strong conclusions at this moment would be premature. Therefore, we would first like to discuss the available results, then propose their interpretations in the context of IST and RDS theories.Among non-problematic pornography users, an inverse relationship between right striatum (more precisely caudate) volume and frequency of pornography consumption was observed . The samOf the other studies not strictly related to cue or reward processing, Banca et al. showed decreased ventral striatal activations among CSB subjects when compared to controls as a response to lack of erotic or monetary reward in a conditioning task . KluckenIf we focus strictly on ventral striatum activity in all the above mentioned studies, then a consistent schema of results emerges: preferred erotic pictures , expliciTo examine published results in the light of RDS, we need to look at the differences in ventral striatal activations between CSB  and control groups. RDS predicts hypoactivation for rewarding stimuli and for cues predicting such stimuli in between group comparison. None amongst the four studies examining reactivity for erotic stimuli –39 indicFrom our point of view, it is worth investigating whether CSB can be distinguished into two subtypes characterized by: (1) dominant interpersonal sexual behaviors, and (2) dominant solitary sexual behaviors and pornography watching , 49. BasAccording to IST, learned cues  related to addiction evoke increased responses in the ventral striatum and evoke increased motivated behavior  among addicted individuals, while responses to the reward itself remain unchanged or undergo blunting over time , 31. ThuReading each of the presented publications –39 separper se is a rewarding stimuli , which increase sexual arousal and lead to masturbation ending with orgasm (reward). But in the research , we obse stimuli .Most recent meta-analysis  of 25 stThe amount of available studies on CSB  is constantly increasing. Among currently available studies, we were able to find nine publications Table  which utThe current state of the data allows us to conclude that CSB is related to increased ventral striatal reactivity for erotic stimuli and cues predictive for such stimuli. However, many basic questions allowing for direct comparisons with substance addictions and pathological gambling remain unaddressed. We see a need for studies directly comparing CSB individuals with populations addicted to substances (to verify predictions based on RDS) as well as more experimental work on cue and reward processing in CSB (for further verification of predictions based on IST). Future studies should also try to control for dominant patterns of CSB .We also want to note that the ventral striatum is only one brain region related to reward processing and learning, and that a much more complex picture of CSB can be presented when we are able to integrate knowledge on whole brain activity.Our review has limitations related to the small number of fMRI research with CSB patients. Due to this limitation, we tried to include all studies, despite obvious differences in the diagnostic methods, and criteria they imply (see Table 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.


Athletes who wish to resume high-level activities after an injury to the anterior cruciate ligament (ACL) are often advised to undergo surgical reconstruction. Nevertheless, ACL reconstruction (ACLR) does not equate to normal function of the knee or reduced risk of subsequent injuries. In fact, recent evidence has shown that only around half of post-ACLR patients can expect to return to competitive level of sports. A rising concern is the high rate of second ACL injuries, particularly in young athletes, with up to 20% of those returning to sport in the first year from surgery experiencing a second ACL rupture. Aside from the increased risk of second injury, patients after ACLR have an increased risk of developing early onset of osteoarthritis. Given the recent findings, it is imperative that rehabilitation after ACLR is scrutinized so the second injury preventative strategies can be optimized. Unfortunately, current ACLR rehabilitation programs may not be optimally effective in addressing deficits related to the initial injury and the subsequent surgical intervention. Motor learning to (re-)acquire motor skills and neuroplastic capacities are not sufficiently incorporated during traditional rehabilitation, attesting to the high re-injury rates. The purpose of this article is to present novel clinically integrated motor learning principles to support neuroplasticity that can improve patient functional performance and reduce the risk of second ACL injury. The following key concepts to enhance rehabilitation and prepare the patient for re-integration to sports after an ACL injury that is as safe as possible are presented: (1) external focus of attention, (2) implicit learning, (3) differential learning, (4) self-controlled learning and contextual interference. The novel motor learning principles presented in this manuscript may optimize future rehabilitation programs to reduce second ACL injury risk and early development of osteoarthritis by targeting changes in neural networks. Injuries of the anterior cruciate ligament (ACL) are one of the most common and devastating sports injuries. The short-term physical and psychosocial consequences of an ACL injury are significant. Athletes experience limitations in daily life and reduction in sports participation. ACL injuries are also associated with long-term clinical sequelae that include meniscal tears, (osteo-)chondral lesions, and an increased risk of early onset of osteoarthritis –3. TreatFor young athletes (< 25 years of age) returning to competitive sports involving jumping and cutting activities, second ACL injury rates of 23% have been reported, especially in the early return-to-sport (RTS) period . Based oMotor learning is defined as the process of an individual’s ability to acquire motor skills with a relatively permanent change in performance as a function of practice or experience . The curExternal focus of attention.Implicit learning.Differential learning.Self-controlled learning and contextual interference.The following key concepts may enhance rehabilitation by targeting movement asymmetries and prepare the patient for re-integration to sports after an ACL injury that is as safe as possible:In almost any rehabilitation situation where motor skills are to be (re-)learned, patients receive instructions about the deemed correct movement technique. These instructions typically refer to the coordination of the patient’s body movements, including the order, form, and timing of various limb movements.Instructions that direct the patient’s attention to their own movements induce an internal focus of attention . For exaHowever, a growing body of evidence shows that this type of attentional focus may not be as effective as previously thought . InteresRecent work has begun to shed some light on the neural mechanisms of attentional focus, demonstrating that external focus instructions increase intracortical inhibition, providing neurophysiologic support for the constrained action hypothesis . As cortRecent work has also demonstrated the applicability of using an external focus of attention during rehabilitation after ACLR to improve movement skill acquisition that can reduce secondary ACL injury risk . PatientIn addition to jump-landing motor control, postural stability deficits were shown to also be a risk factor for sustaining a second injury after ACLR . As suchExamples of internal and external focus instructions Figs.  and 2 arThe aim of implicit learning methods is to minimize the amount of declarative (explicit) knowledge about movement execution during learning. For this purpose, implicit learning can be induced by providing analogies rather than explicit instructions during the acquisition of motor skills . AnalogyImplicit learning reduces the reliance on the working memory and promotes more of an automatic process . It is fOne of the most interesting and widely unexplored aspects of implicit learning in rehabilitation is its connection with anticipation and decision making. This may be important in the late stages of rehabilitation when the patient is approaching the RTS phase. An athlete should be progressively exposed to physical, environmental, and psychological stressors that are comparable to those they will be exposed to in the sport they participate in. In light of secondary ACL injury prevention, training in this phase of the rehabilitation process should emphasize motor control factors such as anticipation, responses to perturbation, and visual-motor control within complex task environmental interactions. Implicit training using limited visual information improves athletes’ anticipatory skills . In contVarious studies pertaining to the neural mechanisms related to implicit motor learning have been conducted revealing a unique neural network associated with implicit relative to explicit learning , 41. In In a laparoscopic simulation task, novice participants were assigned to an explicit or an implicit motor learning condition . To deteExamples using analogies and metaphors (implicit instructions) are provided in Table Differential learning is based on the theory of dynamical systems . When usThe nature of the neurophysiological processes underlying differential learning versus repetitive practice has been examined recently in badminton players . The subDifferential learning is not the standard in rehabilitation, which typically consists of one exercise for a predefined number of repetitions and sets, before moving on to the next exercise. However, in most sports it is quite rare to repeat the same movement for 3 sets of 10 repetitions before moving on to another movement, given that athletic activity requires rapid and variable movement performances that can be facilitated with differential learning approaches to therapy design. It is possible that neuroplasticity following ACL injury is in part due to therapy that does not engage differential learning. As Lepley et al.  showed, In most rehabilitation situations, clinicians determine the details of the training session. For example, they decide in which order tasks are practiced, the practice duration, and when or if instructions or demonstrations will be given. Thus, while clinicians generally control most aspects of practice, patients assume a relatively passive role. Self-controlled learning  is a powerful tool in motor learning . An examClinicians can also encourage patients with positive feedback to enhance feelings of success to optimize motor learning. For example, to instruct athletes on the proper jump-landing technique, a recent study employed visual instruction in the form of an expert model performing a jump-landing task . The athThe neuroplasticity associated with self-controlled learning was also apparent in a recent EEG study in which participants were assigned to either self-control or yoked groups and asked to practice a tossing task . Self-coPractice has a key role in the acquisition of motor skills during rehabilitation. Hence, the way the practice is scheduled influences the acquisition of motor skills. Three categories are used to describe variability and practice order: blocked, serial, and random. Traditionally, practice is scheduled in a blocked (constant) fashion. Blocked practice is when an athlete performs a single skill over and over, with repetition being the key. Variance in training is minimized or nonexistent. In serial practice, a certain prearranged series of tasks are repeated and practiced. Random practice involves practicing multiple skills in a random order. Variable practice involves performing variations of the task or completely different tasks throughout a treatment session. For transfer of skill to occur, a review of the literature has suggested that variable practice may be more effective .Contextual interference in motor learning is defined as the interference in performance and learning that arises from practicing one task in the context of other tasks . The amoFor clinical application, skill level of a patient is a factor that may need to be considered in terms of amount of contextual interference provided. During blocked practice there is low interference or disruption in memory as a person practices multiple trials repeatedly. However, in random practice there is high interference because trials are interrupted by other tasks. Study results have shown that while higher contextual interference (random practice) may lead to poor(-er) performance, it frequently leads to better learning (as measured by retention and transfer tests) compared with blocked practice , 67. ThiThe neural substrates of contextual interference during motor learning have been examined in a study with participants assigned to a blocked group or contextual interference group, learning a sequential task with the left hand . Based oContextual interference may provide a unique method to address the visual–motor and sensorimotor specific neuroplasticity after ACL injury as described by Kapreli et al.  and GrooIn a frequently observed injury mechanism, the player is embedded in a situation where external factors such as possession of a ball and position of team mates and opponents are involved . The attRehabilitation programs mainly focus on pre-planned motor skills in a predictable environment with a focus on postural alignment , 74. PraThe purpose of this article is to present perspectives from motor learning to support neuroplasticity applied to clinical settings that have the potential to improve rehabilitation strategies and reduce the risk of second ACL injury. There are many variables to consider when structuring training programs for patients after ACLR, including the type, amount, intensity, and frequency of exercise and the importance of minimizing adverse reactions such as pain or swelling. From a motor learning perspective, people vary in their ability to learn new motor skills .Clinicians should be cognizant that patients need to find an individualized motor solution that works best for them within their specific environmental context and the constraints of their own bodies . In thisA strong link has been demonstrated between acquisition of motor skills and neuronal plasticity at cortical and subcortical levels in the central nervous system that evolves over time and engages different spatially distributed interconnected brain regions .Evidence is emerging indicating the large cascade of neurophysiological alterations that occur after ACL injury. Although considered a unilateral injury, an ACL injury induces bilateral lower extremity dysfunction , 79, witGrooms et al.  posited Use of the principles of attentional focus seems to be very promising in clinical settings. In a systematic review, it was clearly established that using instructions with an external focus resulted in better motor performance and quality of movements (improvements were sustained over time) compared with an internal focus of attention . AdoptinAlthough behavioral studies have clearly indicated that external focus instructions outperform internal focus instructions in learning motor skills, the mechanisms behind these effects are still an area that warrant further research. More specifically, more fundamental research is needed to determine what the underlying brain principles are. The literature is also scarce pertaining to the other principles of motor learning outlined in this manuscript. Our lack of understanding of the neurophysiological processes involved in application of external focus attention applies also to our understanding of the mechanisms involved in implicit and differential learning. Given the reorganization of the central nervous system that takes place after an ACL injury, we need to determine which principles of motor learning could enhance the neuroplastic processes that could translate to motor learning interventions with the goal of optimal function of the patient.The current evidence suggests that an increased risk of a second ACL injury is highly related to asymmetrical joint loading. Current rehabilitation programs appear not to be effective in targeting these aberrant movement patterns. Several novel motor learning principles have been presented in this article. We have provided a continuum of recently developed neuromuscular training programs using novel training methods for high-risk populations, now tailored to target biomechanical and neuromuscular risk factors as identified in patients after ACLR. Future research should focus on which, if any, combinations of the presented novel motor learning principles yield better clinical outcomes. Motor learning should be applied to support neuroplasticity after ACL injury. Because every person (and brain) is different, the optimal solution may require motor learning principles individually tailored to the injured athletes.


Congestive heart failure (CHF) is a debilitating condition that afflicts tens of millions of people worldwide and is responsible for more deaths each year than all cancers combined. Because donor hearts for transplantation are in short supply, a safe and durable means of mechanical circulatory support could extend the lives and reduce the suffering of millions. But while the profusion of blood pumps available to clinicians in 2019 tend to work extremely well in the short term (hours to weeks/months), every long-term cardiac assist device on the market today is limited by the same two problems: infections caused by percutaneous drivelines and thrombotic events associated with the use of blood-contacting surfaces. A fundamental change in device design is needed to address both these problems and ultimately make a device that can support the heart indefinitely. Toward that end, several groups are currently developing devices without blood-contacting surfaces and/or extracorporeal power sources with the aim of providing a safe, tether-free means to support the failing heart over extended periods of time. Congestive heart failure (CHF) is a progressive condition in which cardiac function deteriorates over time. It is most common among people 65 years or older, but practically anyone can be at risk as the causes of heart failure include everything from coronary artery disease, high blood pressure, and congenital heart defects to myocarditis, abnormal heart rhythms, valve disease, diabetes, and obesity. The most common symptoms of the disease include shortness of breath and fatigue, and it is often diagnosed via blood tests, electrocardiograms, echocardiograms, stress tests, coronary angiograms, and chest x-rays  CHF remaCADs are often categorized according to duration of support. If a device lasts from hours to weeks as a means to stabilize patients until longer-term mechanical support can be implemented, it is considered to be a ‘bridge-to-device (BTD)’ . BTDs weCADs may also be used to provide circulatory support to patients on the waiting list for heart transplantation, in which case they are considered to be ‘bridge-to-transplant (BTT)’ devices. While BTT devices do not last longer than 2 years on average, the longevity of CADs is much better today compared to that of the mid-80s where the typical working life of these devices was only about a month . Yet, thIn rare instances that are difficult to predict, some patients recover cardiac function while under CAD support and no longer need heart transplantation. These cases are categorized—more often in retrospect than by design—as ‘bridge-to-recovery (BTR)’ . Currently, the most ambitious unmet goal in the CAD field is to develop a cardiac support system for long-term or permanent use. A safe, reliable, durable, implantable support mechanism leading to the preservation, or even restoration, of cardiac competence and coronary flow that completely frees patients from the need for heart transplantation would be considered an effective device for ‘destination therapy (DT)’ . In ordeThe concept of artificial blood pumps can be traced as far back as 1813 when Le Gallios first performed the task by squeezing rubberized pumping chambers between pairs of wooden planks . The earWhen VADs were first developed, they were designed to replicate the native cardiac cycle and generate pulsatile flow using a diaphragm and unidirectional artificial heart valves A 3]. Th. Th3]. TBecause the left ventricle (LV) and right ventricle (RV) can be supported either separately or in unison, ventricular assistance is commonly separated into LVAD, RVAD, and BiVAD categories . With isThe clinical settings in which RVAD therapy are most commonly employed include acute myocardial infarction, pulmonary embolism, pulmonary hypertension, myocarditis, post-cardiotomy shock, cardiac transplantation, and LVAD implantation. As the frequency of LVAD use continues to rise, this last scenario is becoming increasingly common as nearly half of all CHF patients show right heart failure after LVAD implantation and 4% require RV support within the first two weeks post-operation ,28. BecaWhile the majority of patients retain sufficient RV function throughout the course of LVAD therapy to avoid the need for ancillary support, nearly 48% of LVAD recipients experience sufficient levels of postoperative RV dysfunction to warrant the use of a biventricular assist device . BiVAD iTotal artificial hearts (TAHs) are designed to entirely replace native heart function over extended periods to treat end-stage CHF. The first human TAH implantation was performed in 1969 by Denton Cooley using the Liotta artificial heart as a bridge to cardiac transplantation. The patient was supported on this pneumatic device for three days during which time hemolysis and deteriorating renal function prompted surgeons to replace the pump with a donor heart that failed 36 h later ,19. It wBecause first generation pulsatile pumps were limited by their large size, high noise emission, and durability issues leading to frequent malfunction and morbidity, research to develop smaller and more reliable devices were initiated and continued through the 1990s . As a reThe third generation LVADs are continuous flow centrifugal pumps designed with magnetic and/or hydrodynamic levitation of the impeller with non-contact bearings and its outflow directed perpendicular to the axis of rotation ,34. ThesAfter five-plus decades of dedicated research aimed at developing blood pump technologies to support the failing heart, a cadre of devices capable of delivering different levels of support at different levels of invasiveness are now available to treat different varieties and severities of cardiac malfunction. These range from acute catheter-based interventions used for partial univentricular support to long-term implantable pumps designed to restore normal perfusion levels in both systemic and pulmonary circulations ,18,20. AExtracorporeal membrane oxygenation (ECMO) A is a foAbioMed’s Impella catheter B is an iPneumatic intra-aortic balloon pumps (IABP) C, which Thoractec’s CentriMag acute circulatory support system D, a tempAlthough the Heartmate II axial flow pump remains the world’s most widely used and extensively studied VAD to date with over 26,000 patients implanted for periods up to 10 years and beyond, third-generation centrifugal pumps like the HeartMate III (Thoratec) and HeartWare HVAD (HeartWare) are currently poised to become the device of choice as either BTT or DT for end-stage CHF patients. HeartMate III  was builHeartWare HVAD is a small CF-LVAD with a displacement volume of 50 mL and an output capacity of 10 L/min . It is cSynCardia CardioWest TAH (SynCardia) is the world’s first and only commercially approved total artificial heart that is currently in use today . The mecConventional continuous flow VADs were designed specifically to treat adult patients, who comprise the vast majority of the end-stage CHF population and so tend to be too large for use in pediatric patients weighing less than 25 kg (55 lbs.) . Berlin In spite of the increasing number of VAD options currently available to patients due to revolutionary advances in cardiac support technologies, numerous challenges still persist. Ventricular arrhythmia, right heart failure, infection, pump thrombosis, and bleeding are still areas of concern, as are issues of long-term patient management and a lack of clear guidelines regarding patient eligibility criteria for VAD therapy . DifficuIndeed, given that heart failure has now risen to pandemic proportions across the globe while the availability of donor hearts remains woefully inadequate to meet the rising demand, continued expansion of mechanical circulatory support for use as long-term BTT or DT is considered a clinical necessity. But despite decades of development most VAD therapies are limited to short-term BTT applications due to three longstanding complications. One is bacterial infection from percutaneous drivelines, which is the most frequent LVAD-associated problem . AnotherDevice malfunction, bleeding, thrombosis, and inadequate aftercare all contribute to VAD failure in the clinical setting, but percutaneous driveline infection (DLI) A is one Another significant cause of LVAD complications is thromboembolism B associaThe reported incidence of gastrointestinal bleeding (GIB) C after cThe rate of DLI, thromboembolic incidents, and bleeding problems must be curtailed if long-term cardiac support is to become a viable treatment option for end-stage CHF patients. Toward that end, there have been numerous attempts to eliminate these predominant failure modes and develop an untethered, non-blood-contacting VAD as a destination therapy.To provide long-term CAD patients better quality-of-life, various powering methods have been proposed to minimize or eliminate extracorporeal power requirements that limit patient autonomy and contribute to patient stress over potential power delivery failures  and DLI risk. One of the most interesting attempts was a nuclear-powered device from the 1980s that used Plutonium-238 as a power source. The potential was in the nuclear radioisotope Plutonium that offered the highest possible energy density and long half-life without requiring any energy storage. However, the critical problems of heat dissipation and safety concerns regarding nuclear element leakage eventually led to termination of the project ,87. Another attempt to develop a permanently implanted circulatory support system was based on a small, lightweight spring decoupled C-core solenoid that was first introduced in the early 1980s. This solenoid drive system was used to actuate a pair of preloaded beam springs that directly coupled to a dual pusher-plate blood pump, producing high starting forces and constant pump pressures through repeated ejection strokes. With this technology operating in combination with external plug-ins that included portable and rechargeable lithium-ion, nickel metal hybrid, or lead acid gel batteries, a level of patient mobility similar to that afforded by battery-powered devices available today was achieved ,89. HoweTranscutaneous energy transmission (TET) technology A that trThe inductive electromagnetic TET system B used inThe use of electrically stimulated skeletal muscle as an endogenous power source to drive circulatory support systems is another alternative that is currently under study. An internal muscle energy converter that operates by converting the contractile energy of a muscle into a hydraulic power source would greatly simplify cardiac implants by eliminating electromechanical components and avoiding the need to transmit energy across the skin ,103. A dThe concept of muscle-powered cardiac support is not new. The use of untrained skeletal muscle to aid the failing heart dates way back. In 1935, Beck and Tichy employed static muscle grafts to revascularize the myocardium . And in The recent development of a functional muscle energy converter (MEC), which operates by converting endogenous muscle energy into hydraulic power, may ultimately provide CAD developers with the means to harness the body’s own energy to assist the failing heart over the long term ,103. Amocopulsation) or diastole (counterpulsation). Copulsation enhances cardiac output by increasing pulse and arterial pressure during systole, while counterpulsation boosts heart function by reducing aortic pressures as the heart fills thereby providing lower cardiac afterload for the failing heart [Despite innumerable CAD designs and material modifications made over the decades in an attempt to eliminate chronic pump thrombosis, the situation still persists while the precise dosage and frequency of long-term antithrombotic therapies remain ambiguous ,21. Consng heart . These tng heart . But, abA normal heart with a ventricular ejection volume of about 71.5 mL per beat (CO = 5 L/min and HR = 70 bpm) has a ventricular ejection fraction (EF) of 60%. While a healthy heart’s EF ranges from 55% to 70%, anything less than that is considered mild (<54%) to severe (<35%) heart failure. One way to boost the EF of a defective heart is by applying pulsatile pressure to the epicardial surface in synchrony with the natural ventricular contraction. Copulsative biventricular compression devices have been around for decades. The Anstadt Assistor Cup became the first successful direct cardiac compression sleeve (DCCS) in 1991 and Dr. DeBakey’s pneumatic LV compression cup was first implanted in 1996 ,21,109. Recently, researchers have turned to emerging soft robotic technologies to improve the long-term functionality of DCCSs. In 2017 for example, a silicone molded sleeve A that emAnother form of circulatory support for CHF patients that provides effective cardiac unloading and patient stabilization is displacement of blood from the aorta during the diastolic phase of the cardiac cycle. This technique is most often performed clinically using an IABP that is implanted and inflated inside of the descending aorta as previously described. This mechanical support augments diastolic pressure and coronary circulation via balloon inflation and reduces the resistance to systolic output via the presystolic deflation of the balloon ,59,115. Passive periventricular restraint, which involves wrapping the entire epicardial surface with a sleeve-like prosthetic to provide circumferential diastolic support to the failing heart, is an approach that evolved from a surgical procedure known as cardiomyoplasty (CMP) in which the ventricles were wrapped with the latissimus dorsi (LD) muscle flap and stimulated to contract in synchrony with the systolic portion of the cardiac cycle. While CMP was effective in reducing wall stress, myocardial oxygen consumption and adverse ventricular remodeling, these benefits were found to persist in some patients even after the muscle flap stopped contracting, which suggested that these same effects might be produced via passive ventricular restraint alone. Toward that end, several passive prosthetic devices were developed to produce the same effects without resorting to the surgical complexities and post-surgical complications involved with LD flap isolation and subsequent transplantation into the chest. Corcap  and Paracor HeartNet were two such devices that were designed to act more like the passive LD flap insofar as pressure was applied uniformly across the ventricular free walls. The Acorn sleeve was a flexible, polyethylene-terephthalate mesh that was placed around the heart through a median sternotomy to provide end-diastolic support and reduced wall stress . The ParKey characteristics of the large and expanding family of cardiac assist devices developed in the past, used in the present and slated for the future are summarized in Since 2001 when the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial became the landmark study that established the benefits of implantable, pulsatile, and permanent VAD therapy in patients with late stage CHF, survival rates have improved to nearly 80% one-year after primary implantation due to a combination of refinements in patient selection strategy, surgical techniques, and peri-operative management ,131,132.Since its inception in the early 1960s, a remarkable amount of research and development has been performed in an effort to improve and expand the field of cardiac assist devices. As a result, a wide array of cardiac assist technologies is available to clinicians today, each with their unique set of strengths and weaknesses, but all designed with one common goal in mind: to provide safe, reliable circulatory support however and whenever it is needed. Of course, these challenges grow larger as rising levels and durations of support are required and it is important to continue to seek solutions that will free these patients from persistent physical risks and psychological distress. Toward that end, reducing device-related complications and eliminating the loss of freedom imposed by percutaneous tethers will be key factors in developing CADs that are truly suitable for long-term or permanent use. In addition, replacing current patient management practices with physician–patient interface systems that are more systematic, convenient, and effective will likely play a big role in improving the lives of CHF patients who must rely on life-sustaining devices for years on end. Fortunately, there is reason to expect that many of these improvements will be implemented in the not-too-distant future as steps to meet these challenges are currently being taken by several groups working to develop effective destination therapies with longer patient survival times and improved quality-of-life.


Firmicutes in intestinal sections from these bats. The authors use a previously published approach of sequencing 16s rRNA for taxonomic assignment of the microbial community  gut microbiome composition is closely associated with host phylogeny. They provide evidence that feeding-strategy plays a role in the microbiome composition of these bats  are a class of microorganisms that include phytoplasmas (‘Candidatus Phytoplasma’) that are being increasingly recognized for their role in plant diseases such as sapodilla little leaf, yellow leaf roll disease of peach, strawberry green petal and sugarcane white leaf syndrome. These diseases affect a diverse array of economically and ecologically important plant hosts around the world (Vesterinen et al., Mollicutes are highly diverse and are made up of five orders, Acholeplasmatales, Anaeroplasmatales, Entoplasmatales, Haloplasmatales, and Mycoplasmatales. All members of these orders are obligate parasites. Genera ‘Candidatus Phytoplasma’ and Spiroplasma, from the Order Acholeplasmatales and Entoplasmatales, respectively, consist of plant pathogens. ‘Candidatus Phytoplasma’ and Spiroplasma represent 18% of the Class Mollicutes (Zhao et al., Candidatus Phytoplasma’ consists of over 40 species that are known to be pathogenic in plants (Miyazaki et al., Spiroplasma, at least two species have been identified as plant pathogens, Spiroplasma citri, the causative agent of citrus stubborn disease (Saglio et al., Spiroplasma kunkelii, which is associated with corn stunt disease (Whitcomb et al., ‘Artibeus jamaicensis have the highest relative abundance of Mollicutes in their intestinal contents (Carrillo-Araujo et al., Firmicutes in all bat species that were sampled. Looking at their data from a plant disease perspective, we wondered if frugivorous and nectivorous bats could play a role in the transmission of plant pathogens. Could this data set and the sampling methods established allow us to monitor bats as sentinels of plant pathogens? Here, we speculate upon the role of frugivorous and nectivorous bats as possible vectors of plant pathogens. We outline limitations of this study that do not allow us to fully establish the dynamics of plant pathogen-bat interactions. We also discuss future directions to firmly establish the role of bats as potential vectors of plant pathogens.In their article, the authors indicate that A. jamaicensis (Figure Carollia perspicillata (Figure Leptonycteris yerbabuenae (Figure Glossophaga soricina (Figure Mollicutes into two major branches occurred about 470 MYA, placing phytoplasmas and their closest ancestor, Ancholeplasma in the same branch (Maniloff, Acholeplasma-like ancestor around 99 MYA (Zhao et al., Recently, bats have been implicated as the reservoirs of several emerging viruses that cause serious disease in humans and agricultural animals (Calisher et al., s Figure  and Caroa Figure  and necte Figure  and Glosa Figure  that werMollicutes from bat intestinal samples would identify if these bacteria remain viable while they pass through the harsh environment of the digestive tract. Unfortunately, many of the plant pathogenic Mollicutes, including phytoplasmas, are unculturable in axenic media. Although Mollicutes are unlikely to replicate in bat gut cells, they could potentially proliferate within the intestinal micro-community. However, this remains to be tested.Multiple studies have established the role of bats as reservoirs of certain mammalian viruses (Corman et al., Other questions about the possible excretion of viable bacteria through bat guano and the ability to infect plants remain unknown Figure . Seeds cWhile bats are speculated as reservoirs of multiple microbes, this study brings up the possibility of using bat microbiome data as predictors of pathogen spread and prevalence Figure . AlthougMollicutes in the intestinal content of Phyllostomid bats opens up an alternate and intriguing line of investigation in to wildlife vectors and sentinels of plant pathogens.Future studies focused on identifying neglected vectors of plant pathogens will elucidate the likely role played by herbivorous wildlife in the dispersal of these microorganisms. Results from such studies will have agricultural policy implications for plant diseases. Phytoplasmas continue to cause losses to local farmers and has an impact on the economy. In our opinion, this study by Carrillo-Araujo et al. that identified AB and EP-L wrote the commentary. KM edited the commentary.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.


Animal signals—involving combinations of acoustic, chemical, visual, and behavioral cues—are among the most diverse traits in nature. Testing hypotheses about signal evolution has been hampered by difficulties with comparing highly divergent signals among species. In this Primer, I describe recent advances in capturing signals and studying their evolution. I highlight new findings using an information theory–based approach to quantifying signal variation in the diverse birds-of-paradise. Growing access to signal databases in tandem with development of new analytical tools will open up new avenues for studying the proximate mechanisms and ultimate evolutionary causes of signal variation, both within and among species. Animals communicate with each other in diverse ways–using chemicals, sounds, colors and movement. This Primer explores research on animal signals and highlights the need for advances in studying how complex signals evolve, such as that described in a recent PLOS Biology paper. Animals communicate with each other in diverse ways, including chemicals, sounds, colors, and movement. Development of a theoretical framework for how signal traits coevolve with preferences in the 1990s led to a burst of research on the mechanisms and diversity of animal signals , developElaborate ornaments and signals—like peacock trains and anole dewlaps—are among the most diverse traits in nature. Signal traits provide unique opportunities for studying trait evolution more generally for two important reasons. First, animal signals are complex, varying spatially , temporally , and qualitatively . Second, signal traits are a classic system for studying how sexual selection works because of the increased strength and constancy of sexual selection compared to natural selection  and the Early research into animal signals involved the use of standard color swatches or phonetic renderings of bird songs . In the last 30 years, technological advances in, and falling prices of, devices to quantify signals numerically   have driPLOS Biology [A new paper in this issue of  Biology  uses novLycocorax pyrrhopterus) with a uniformly glossy-black plumage would have a lower visual complexity score than the red bird-of-paradise (Paradisaea rubra), a species with an iridescent green throat, red tail, yellow head, and brown back and wings. This composite approach gets around the problem of incomparability in complex signal traits and lets the authors ask the question: How does signal complexity itself change over evolutionary timescales?A challenge with variable datasets  is comparing different signals among species. For example, how can we compare a whistle in one species to a chirp in another species? Ligon and colleagues  tackle tEvolutionary tradeoffs involving reduced expression of one trait in response to elaboration of another trait are commonplace in nature. Darwin  first diBy analyzing signal complexity in unprecedented detail, Ligon and colleagues  uncover Form–function relationships are well studied in ecological traits  but lessExciting discoveries about how genetic mutations translate to brilliant signals, like red feather ornaments in birds, are now being made with next-generation sequencing technology and genome-wide association studies . ComparaStudying the evolution of single traits shared by a group of closely related species is relatively straightforward. Increases in the number of traits necessary to capture variation in complex signals bring new analytical challenges associated with multivariate datasets. For example, as a general rule of thumb, the number of traits should not be greater than the number of species used in a comparative analysis . Recent Recent work has focused on coevolution of signals and sensory systems or how sensory systems might evolve for optimal perception of signals . However


This review shows over 300 compounds isolated and identified from plants that previously demonstrated anti-inflammatory activity. They have been classified in appropriate chemical groups and data are reported on their pharmacological effects, mechanisms of action, and other properties.


Recently, there has been an increasing number of studies on exceptional cognitive aging. Herein, we aim to objectively provide the operationalized characterization of older adults with unusually high memory ability. Some authors have defined them as “SuperAgers”, individuals aged 80 years or older with memory ability similar or superior to middle-aged subjects. On the other hand, the terminology “high-performing older adults” (HPOA) seems to appropriately conceptualize these individuals without exaggeration. A threshold for age is not a reliable criterion, but may be defined as 75 and 80 years of age for developing and developed countries, respectively. We propose that HPOA may exhibit episodic memory test scores equal to or greater than those of individuals aged 50-60 years, according to the validated tables for the respective country. This group must also have global cognition scores within expected average values for age and education. Executive functioning may play a central role in the exceptional memory performance of this group. Further studies are essential to confirm existing findings and may provide important evidence for cognitive aging theory and the neurobiology of dementia. Despite the growing effort in uncovering the underlying pathophysiology of this alarming disease, therapeutic failure has been found to be 99% in all clinical trials.,--Notably, these older adults exhibit similar features to middle-aged individuals.In this setting, the aim of the present study was to propose an evidence-based opinion of an operationalized definition of individuals who achieve successful cognitive aging and to determine the inclusion criteria for this group, particularly in developing countries.,,As described by Depp et al.,In this context, perhaps the most popular terminology, “SuperAgers”, is defined by individuals aged 80 years or over, with a memory ability similar or superior to middle-aged subjects.Although this definition is useful in defining older adults with exceptional cognitive ability, we believe it to be rather limited. The evaluation of individuals with high performance does not imply only selecting a single class of subjects with a specific neuropsychological criterion. A broader, more comprehensive definition should also include subjects with little or no literacy but with unusual cognitive functioning. Therefore, the definition of SuperAgers might be inadequate for developing countries, due to the high prevalence of low education and its influence on normative values of cognitive tests. Thus, many individuals who are not classified as SuperAgers, but have exceptional memory ability for age and education, might be misclassified as usual agers.-There is a significant effort to elucidate the aging process by studying cognitively average older adults. Selection criteria of many studies includes older adults without signs of cognitive decline.,,,,,We propose a general nomenclature for individuals who achieve successful cognitive aging. The term “High-performing older adults” (HPOA), first cited by Cabeza et al.,,,,An adequate age criterion is vital for proper selection of older individuals with high cognitive performance. Different age criteria are used by different authors, ranging from 60 to 80 years.,The concept of aging is cultural and dynamic. The onset of old age is a matter of discussion, with a massive impact on public health policies, labor force, and retirement. Conventionally, aging is arbitrarily determined as occurring at 65 and 60 years of age in developed and developing countries, respectively.,-Age-related cognitive decline usually intensifies at around 60-65 years of age-The HPOA age cut-off may vary according to sociodemographic and cultural characteristics. We propose a threshold of successful cognitive aging according to sociocultural characteristics of the studied sample. An adequate, though imperfect, cut-off could be determined for the developed and developing countries as 80 and 75 years, respectively. These proposed cut-offs account for the 5-year difference both in life expectancy and in the definition of older adults between developed and developing countries, as previously cited in this topic. Furthermore, developing countries have lower educational levels and higher social discrepancy than developed countries. Thus, a higher age threshold may incorrectly select individuals with a better educational and economic background in these nations.-The extent of usual, age-related cognitive decline implies a subject’s ability for independence and functioning in daily life. The processes of memory encoding, storage, and retrieval decline over the course of the whole lifetime, where encoding is particularly vulnerable to aging and seems to decline across the lifespan.,,,Several studies regarding high performance in old age rely upon episodic memory evaluation as a major defining factor.,,There are several validated and reliable tools for episodic memory measurement in the English language. Specifically, psychometric properties for Brazilian neuropsychological tests lack diversity and adequacy of data. The Rey Auditory-Verbal Learning Test (RAVLT), typically applied in older adults, reliably distinguished not only high-performing groups from controlsThere are many factors that must be considered when choosing the adequate neuropsychological test to measure episodic memory capacity. The major factor in considering any test is the development of normative data for the studied population. There are many suitable tests developed specifically for measuring verbal memory , such asAs defined in previous studies, HPOA must represent the highest level of memory performance in elderly. Some studies define the top 20% of the sample as high memory performers, which may introduce a bias. This method selects only high performers in a single sample, which may not adequately represent the high-performing individuals in the general population as a whole.Nonetheless, the rigid memory score definition used by Rogalski et al.,,Global cognition must also be evaluated in order to successfully select individuals with excellent memory performance. A low score on this type of test may indicate a subclinical pathologic process that does not affect the memory system. On the other hand, above average scores suggest that these individuals have an optimal performance when associated with unusually high memory scores. It is important to note that the cognitive evaluation typically performed in a neurological or psychiatric routine is essentially not a measure of global cognition. Some tools for dementia screening are excellent for the diagnosis of mild cognitive impairment or dementia staging but should be avoided as classifiers for “cognitively normal”, such as the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA).,-,,-,Frontal lobe functioning seems to be particularly vulnerable to aging.,,Processing speed is a strong indicator of age changes in memory abilityA complete understanding of the mechanisms at play in older adults who successfully preserve their memory may reveal key processes in cognitive maintenance. There is still a lack of knowledge in understanding usual and unusual aging. Some recent studies have focused on preclinical stages of Alzheimer’s disease in order to discover early biomarkers of memory decline. The promotion of successful cognitive aging holds great promise in targeting biomarkers, potentially improving cognitive function in later life.The frontal lobe has been shown to be particularly vulnerable to aging and neurodegenerative processes.Some neuropsychological tests are not available in many languages. There is a preference for the evaluation of specific cognitive domains in clinical practice, which may imply a misuse of non-culturally adapted versions of tools. Thus, translation, validation, and development of normative values are needed in order to reliably measure the cognitive functioning of older adults, which must be based on cultural and demographic factors.There is still a need for longitudinal studies on HPOA. Individuals with high cognitive performance may have progressive decline, which is not measurable using a cross-sectional design. In addition, it is not yet known if HPOA cumulate a higher cognitive reserve than usual agers or its relationship to brain maintenance. Only by carefully addressing studies on cognitive aging, will we be able to advance in distinguishing preclinical AD from usual cognitive aging.In summary, in this study we proposed an evidence-based selection criteria for older adults with exceptional cognitive performance. This study plays a role in defining these individuals according to age and cognitive criteria , in cont