Despite a growing literature detailing early childhood risk factors for borderline personality disorder (BPD), few studies have examined moderating factors that might mitigate or exacerbate the effects of those risk factors. The current study examined whether three preschool-age characteristics—impulsivity, emotional lability, and initiative-taking—moderated the relationship between known preschool-age risk factors and adolescent BPD symptoms.n = 151) from the Preschool Depression Study, a prospective longitudinal study with assessments from preschool through adolescence. Preschool risk factors included adverse childhood experiences, internalizing symptoms, and externalizing symptoms measured with parent clinical interviews. Preschool moderating factors were assessed via parent report and observational coding of temperament and behavior. The Borderline Personality Features Scale for Children measured BPD symptoms in adolescence.We performed multilevel modeling analyses in a sample  and moderated the relationship between preschool externalizing symptoms and adolescent BPD symptoms . Greater initiative-taking was associated with lower BPD risk for children with high internalizing or externalizing symptoms. Conversely, for children with low internalizing or externalizing symptoms, greater initiative-taking was associated with increased BPD risk.We found that observed initiative-taking moderated the relationship between preschool internalizing symptoms and adolescent BPD symptoms (We identify a potential moderating factor in BPD development, offer novel targets for screening and intervention, and provide a framework for using early childhood observational assessments in BPD research. Our findings suggest the need for future research on early moderating factors in BPD development, which could inform early childhood interventions targeting those factors to mitigate the effects of potentially less malleable risk factors.The online version contains supplementary material available at 10.1186/s40479-022-00198-6. Borderline personality disorder (BPD) is characterized by instability across multiple domains, including affect, relationships, and self-image, as well as impulsivity associated with frequent risk-taking and self-destructive behavior . BecauseOne key component of BPD prevention is the identification of the most salient risk and protective factors for BPD that could be targeted by early intervention. As is the case with many disorders, early life adversity, parental psychopathology, parenting style, childhood trauma, IQ, childhood temperament, and childhood psychopathology have each been found to predict later BPD diagnosis . More reImplementing interventions earlier in childhood may be critical given recent evidence about the timing of BPD onset. Historically, BPD diagnoses were applied only to adult patients, but recent work has supported the validity of diagnosing BPD in adolescents. Adolescent BPD has been found to be: (a) comparable to adult BPD in the strength of its associations with childhood risk factors, comorbid disorders, and suicidal behavior and ideations ; (b) simGiven that early childhood adversity and psychopathology increase risk for later BPD diagnosis, and that BPD symptoms can emerge as early as adolescence, further work is needed to identify mechanisms for mitigating BPD risk at the earliest developmental point before the disorder’s debilitating symptoms emerge. Despite its robust association with BPD, childhood adversity does not invariably lead to BPD development, as evidenced by recent work examining siblings who experienced similar levels of adversity but were later discordant for BPD , 21. RetThe current study begins to address this gap in the literature by prospectively examining characteristics evident at preschool age that might moderate the relationship between early childhood risk factors for BPD and BPD symptoms in adolescence. We chose from factors that had either been identified as moderating factors in prior retrospective work   or were In adolescence and adulthood, BPD is characterized by both high impulsivity and high lability in negative affect, contributing to the high rates of self-injurious and risk-taking behaviors in this population . SeveralInitiative-taking, which we define as engaging in active coping strategies and seeking out resources in order to meet goals, has received less attention in the BPD literature. Various studies have investigated the role of childhood social support and peer relationships in the development of BPD, with mixed results , 19, 21,In addition to the gap in the literature concerning moderating factors in BPD development, there are also few studies that have employed observational methods to measure aspects of temperament and behavior that might serve as risk and protective factors for BPD. Both parent and observer reports of child temperament and behavior have been shown to demonstrate temporal stability  and predThe goal of the current study was to identify individual-level preschool-age factors that moderate the relationship between childhood adversity and the development of adolescent BPD or moderate the relationship between childhood psychopathology and the development of adolescent BPD. Noting the reliance on retrospective, self-reported data in prior BPD protective factors research, we assessed moderating factors prospectively utilizing both observer and parent reports. We also sought to contribute to the literature on early childhood factors in BPD development by assessing risk and moderating factors in the preschool period (ages 3–5).We hypothesized that parent-reported and observed preschool impulsivity, emotional lability, and initiative-taking would moderate the relationship between preschool risk factors and BPD symptoms in adolescence. Specifically, we predicted that preschool children who had high ACEs, but also demonstrated lower impulsivity, lower emotional lability, or higher initiative-taking, would have fewer BPD symptoms in adolescence than peers exposed to high ACEs who demonstrated higher impulsivity, higher emotional lability, or lower initiative-taking in preschool. We also expected each of these factors to similarly moderate the relationship between preschool internalizing and externalizing symptoms and BPD symptoms in adolescence.t = -1.04, p = .30), ACEs , average internalizing symptoms , average externalizing symptoms , parent-reported  or observed impulsivity , parent-reported  or observed emotional lability , or parent-reported  or observed initiative-taking  from participants in the original sample who did not complete this assessment.Participants were 151 children who were enrolled in the longitudinal Preschool Depression Study at the Washington University School of Medicine in St. Louis Early Emotional Development Program, which prospectively investigated associations between childhood factors and later outcomes. Participants were initially recruited during the preschool period (ages 3–6) from daycare and primary care centers in the St. Louis region, and the final sample of 306 children was selected after oversampling for higher depressive and disruptive the symptoms based on scores from the Preschool Feelings Checklist . ParticiOur choice of early childhood risk factors was based on prior work by Geselowitz et al. , who repM = 8.66, SD = 1.10, Range = 5–10).Consistent with past work in this sample, we used an ACEs measure described by Luby et al.  and BarcOur internalizing psychopathology measure was calculated by summing symptom scores assessing generalized anxiety disorder, separation anxiety, and post-traumatic stress disorder from the parent-reported Preschool Age Psychiatric Assessment (PAPA)  at each Observer ratings of early childhood moderating factors were obtained through coding of Preschool Laboratory Temperament Assessment Battery (Lab-TAB) tasks . Lab-TABMake the Car Go: the child and experimenter raced wind-up cars on a model racetrack; (2) Popping Bubbles: the child blew bubbles with a bubble gun and popped the bubbles; (3) I’m Not Sharing: the experimenter did not share toys with the child and took more and more of the child’s toys; (4) Empty Box: the child was left alone to open a wrapped gift box only to discover there was no gift inside. At the end of each frustration task, the experimenter rectified the situation by apologizing and giving the child toys or a new present.Participants in the current study completed at least one of four Lab-TAB tasks during preschool assessments: two excitement-inducing tasks and two frustration-inducing tasks. In brief, the tasks proceeded as follows: (1) Teams of five to six research assistants blind to the child’s diagnostic characteristics coded videotapes of each task, rating participants’ facial, verbal, and bodily expressions of affect and rating behavioral dimensions including impulsivity, initiative, sociability, and activity level. Ratings were given based on a coding guide developed and adapted from the original preschool Lab-TAB manual  by reseaParent ratings of early childhood moderating factors were obtained from the MacArthur Health and Behavior Questionnaire—Parent Version (HBQ)  during tObserved impulsivity was calculated as an average of observer-rated impulsivity and activity level across the four Lab-TAB tasks and both preschool assessments. Higher impulsivity was defined as acting without thinking, including interrupting, invading others’ personal space, and grabbing objects. Activity level was rated on a scale between sitting completely still and constantly moving. These definitions are comparable to the DSM-5 hyperactivity/impulsivity criteria for ADHD diagnosis  and to mParent-reported impulsivity was calculated as an average of HBQ impulsivity subscale scores across preschool assessments. Items on this subscale assess both inhibitory control and hyperactivity. The HBQ’s impulsivity and inattention subscales have demonstrated high validity in terms of identifying children with clinical symptoms of ADHD .Observed emotional lability was calculated as a function of observer-rated negative affect (anger and sadness) from the two frustration-eliciting Lab-TAB tasks. These tasks were coded in segments, such that one code for each dimension of affect was given in each of the following periods: before the frustrating event occurred, after the frustrating event occurred, and after the situation was rectified. Anger/frustration criteria included tense facial features, forceful body movements, yelling, and angry verbal content. Sadness criteria included downturned mouth, slumped shoulders, crying, and sad verbal content.In order to quantify observed emotional lability, we sought to assess the amount of change in negative affect over the course of the frustration tasks. We decided to use the mean of squared successive differences (MSSD) approach, which in past work has been used to quantify emotional lability using self-reported negative affect , 61. FirParent-reported emotional lability was assessed with items chosen from the depression and oppositional-defiant subscales of the HBQ, leading to sum scores for each preschool assessment of which we took the average to create a final variable. The items chosen were: ‘unhappy, sad, or depressed,’ ‘cries a lot,’ ‘has temper tantrums or hot temper,’ ‘is easily annoyed by others,’ and ‘angry and resentful.’ These items were chosen to reflect both the negative emotionality and affective lability components of the emotional lability construct.Observed initiative-taking was calculated as an average of observer-rated initiative and sociability across the four Lab-TAB tasks and both preschool assessments. Higher initiative during the task was defined as making suggestions for play, asking for a turn, and trying to rectify an unfair situation. This measure represents intrapersonal active coping and is consistent with prior work that operationalized preschool initiative as self-starting, information seeking, and persisting during problem solving . Higher Parent-reported initiative-taking was calculated as an average of HBQ social withdrawal subscale scores across preschool assessments. This subscale assesses the extent to which the child avoids, withdraws from, or is shy around peers and adults. We reverse coded scores so that children with higher social withdrawal scores were coded as lower on initiative-taking. Assessments of parent-reported initiative-taking were limited in the Preschool Depression Study, and while we recognize that this subscale is not a comprehensive measure of initiative-taking, this measure could clarify whether interpersonal coping alone plays a protective role against BPD development, or if both intrapersonal and interpersonal coping strategies are necessary.Adolescents (ages 14–21) self-reported BPD symptoms using the Borderline Personality Features Scale for Children (BPFS-C) , which hLevel 1:Level 2:First, in order to replicate past associations between preschool risk factors and adolescent BPD symptoms found by Geselowitz et al.  using a In order to leverage the nested measurements of each risk factor . All analyses were conducted using R statistical software, version 4.2.0 , pcorrected < .001), internalizing symptoms , and externalizing symptoms .Each of our three risk factors assessed at the initial timepoint (an average of over 13 years later), were significantly associated with future BPD symptom scores, controlling for age, sex, and changes in the risk factors across time Table . More spr(149) = .24, p = .004) as were observer- and parent-reported initiative-taking (r(148) = .21, p = .01). Observer-reported emotional lability was not significantly correlated with parent-reported emotional lability (r(141) = .03, p = .72). Correlations between study variables are shown in Table Next, we examined the magnitude of the association between each of the parent- and observer-reported moderating variables. The correlations varied from insignificant to small. Observer- and parent-reported impulsivity were positively correlated  and parent-reported lability  were significantly associated with initial ACEs scores.Lastly, we examined if any of our parent- and observer-reported measures moderated the association between the initial risk factors and future BPD symptom scores. For the models including initial ACEs, no significant interactions emerged Table . ACEs web = 0.61, 95% CI , pcorrected = .011) and parent-reported lability . Then, in the model with initiative-taking, an interaction emerged . For children scoring high on internalizing, scoring one standard deviation higher than average on observer-reported initiative-taking appeared to be protective, as their BPD symptom scores were lower than those scoring average or lower than average on observer-reported initiative-taking. In comparison, for children scoring low on internalizing, having higher than average observer-reported initiative-taking scores was associated with higher BPD symptom scores compared to children scoring average or below average on observer-reported initiative-taking.For the models including initial internalizing symptom scores, internalizing was still associated with future BPD symptom scores while controlling for each of the moderating variables Table . Additiob = 4.13, 95% CI , pcorrected < .001) and parent-reported lability . However, in contrast to the baseline models, childhood externalizing was no longer associated with future BPD symptom scores when controlling for impulsivity measures  or emotional lability measures . In the model with initiative-taking, childhood externalizing was once again significantly associated with future BPD symptoms , and a similar interaction effect emerged to that found for internalizing symptoms . For children scoring high on externalizing, scoring one standard deviation higher than average on observer-reported initiative-taking again appeared to be protective. In comparison, for children scoring low on externalizing, having higher than average observer-reported initiative-taking scores was associated with higher BPD symptom scores compared to children scoring average or below average on this variable. Lastly, for the models including initial externalizing symptom scores, a number of significant associations emerged Table . In the , 95% CI .91, 4.57The current study sought to identify factors that might moderate the association between known preschool-age risk factors and adolescent BPD symptoms and serve as potential targets for early intervention. The moderating effect of observed initiative-taking most closely matched our hypotheses, in that preschool children who had higher levels of internalizing or externalizing psychopathology symptoms and higher levels of observed initiative-taking had fewer BPD symptoms in adolescence than children with higher levels of psychopathology symptoms and lower levels of observed initiative-taking. This finding suggests that higher initiative-taking, which we defined as active intrapersonal and interpersonal coping and resource seeking, may act as a buffer against BPD risk for children placed at higher risk due to their psychopathology symptoms. An unexpected finding, though, was that among children with lower levels of internalizing or externalizing symptoms, higher levels of observed initiative-taking were associated with more BPD symptoms in adolescence. It is notable that these patterns held for both internalizing and externalizing symptoms, and that in both cases, higher initiative-taking was protective only for children who later went on to have symptom scores near or beyond the BPFS-C symptom cut-off point for presumptive BPD diagnosis. While it is reasonable that initiative-taking could help children high in psychopathology symptoms by expanding their active coping repertoire and connecting them to helpful resources, further work should explore why high initiative-taking might add risk for children low in psychopathology symptoms.Also of interest are our correlational findings, which suggest that our observed measures were distinct from parent-reported measures and are worth exploring in future BPD development research. Our observed measures were at most modestly correlated with parent-reported predictor and moderator measures, indicating that our observed measures likely captured different aspects of temperament and behavior than these other measures. As Stifter et al.  summarizSeveral of our hypotheses were not supported. It is unclear whether this lack of support stems from a genuine lack of moderating effects, or if some of our measures failed to fully capture the underlying constructs. A key limitation of the current study was that our choice of measures for the proposed moderating factors was limited to the assessments conducted at the outset of the Preschool Depression Study, many years prior to the current study, so we were at times unable to choose measures that would be ideally suitable for exploring our hypotheses. For instance, a more relevant parent-reported measure of initiative-taking might include questions about the child’s problem-solving and social-support-seeking behaviors. Additionally, even though we did find a significant moderating effect of observed initiative-taking, an even more relevant measure of observed initiative-taking might assess specific problem-solving behaviors in a task designed to offer multiple opportunities for problem solving, such as a puzzle task where the child could choose to consult an instruction manual or ask for help. Future work would benefit from measures specifically designed to assess our moderating factors, to ensure that nonsignificant results stem from genuine null effects and not from methodological imprecision.It is also notable that when assessing only individual-level characteristics as moderating factors, there were no significant moderators of the effect of preschool ACEs on adolescent BPD symptoms. As such, it is worth considering whether interpersonal-level or environmental-level factors might have more potential for moderating BPD risk pathways. Future work could examine interpersonal-level and environment-level factors suggested to be moderating factors in BPD development in past retrospective work, such as validating parenting , attachmDespite the constraints of the measures used, the methodology employed in the current study represents a strength that could inspire new lines of research on BPD development. To our knowledge, there are few other studies that have examined moderating factors in BPD development using prospective, longitudinal data and incorporating both parent reports and laboratory observations of children during preschool. The current study makes a significant contribution to the study of early childhood (preschool-age) precursors of BPD, an area of research that is still largely underdeveloped, as most prior research examining BPD development has done so using school-age or adolescent assessments of risk factors. Our results further underscore the importance of examining patterns of risk at this early age, as well as the potential need for early screening and intervention in children as young as three years old.An additional strength of the current study is our exploration of initiative-taking, which has rarely been examined in the BPD literature. Adaptive coping strategies and interpersonal skills have been examined in past work on BPD, but not often as part of a unified construct, and not often in early childhood. Initiative-taking stands in contrast to our other potential moderating factors in that it is an adaptive skill that could be enhanced to promote resilience, rather than a maladaptive trait or behavior to be reduced to lessen risk. It is also novel that our observed measure of initiative-taking, which emerged as a significant moderator of risk in two analyses, was comprised of ratings of observed problem-solving, self-starting, and sociable behaviors, rather than self-report ratings of mental processes like cognitive reappraisal and acceptance. The observable nature of our measure facilitates assessment in early childhood, though further work should also explore the mental processes and coping strategies underlying these observed behaviors.Although not a significant moderator in the current set of analyses, the application of the mean of squared successive differences (MSSD) method  in the coding of cross-sectional observational data to create an observed emotional lability measure is a novel addition to the BPD development literature that could be extended to other studies. This measure allows for the observation of lability of negative affect, not just total negative affect, in young children via behavioral coding of two short, standardized frustration tasks staged in the laboratory, the classroom, or various other settings. Our assessment technique can also transfer to other age groups, given that the MSSD of negative affect can be calculated with observations of other age-appropriate frustration-inducing tasks. Our observed measure may be particularly important given the lack of a correlation between observed and parent-reported emotional lability. Using observed measures of emotional lability may provide a new perspective on lability not often captured in the BPD literature, and should be explored in future work.Our findings that levels of initiative-taking in preschool children significantly affected their risk for later development of BPD points to the need for attention to early risk characteristics and potential interventions in the preschool period. If further work replicates our finding that initiative-taking buffers the effect of high psychopathology symptoms on later BPD symptoms, a critical next step would be developing and testing interventions that foster intrapersonal and interpersonal active coping strategies in early childhood. Some prior work already indicates the importance of active coping for reducing BPD symptoms: for example, patients with BPD who showed improvements in problem-solving over the course of treatment were shown to have better treatment outcomes , and theWe focused on moderating factors at the individual level to identify potential targets for intervention that could be implemented in early childhood and in parallel to family-level and social context interventions, or in place of such interventions when family and broader life circumstances are not easily changed. Early interventions promoting initiative-taking and other potential protective factors could be implemented through classroom-based individual-level interventions, some of which have been shown to improve children’s initiative-taking, emotion regulation, and self-control –74. An aThe current study adds to a limited line of research examining moderating factors in BPD development. Additional work utilizing prospective, longitudinal data and multiple reports will be needed to continue to identify factors in early childhood – as well as middle childhood, late childhood, and adolescence – that moderate the BPD risk pathway. Ideally, future studies will use measures more suited to the moderators being examined; to this end, we suggest that researchers examining developmental trajectories of psychopathology add BPD-related assessments to their longitudinal studies as early as possible. We also suggest that researchers completing the later stages of such longitudinal studies add a BPD symptom assessment to their adolescent or young adult outcome measures, as they might find that more of their sample than predicted endorses a high number of BPD symptoms. Intervention studies assessing the effects of Parent–Child Interaction Therapy, classroom interventions, and other early interventions on psychopathology should also consider adding BPD outcome measures to their work to determine if such interventions might mitigate risk for BPD.The current study serves as a starting point for future work on moderating factors in BPD development. Our findings provide evidence for the significant impact of preschool-age initiative-taking on the trajectory of BPD development and imply that fostering active coping and support-seeking in early childhood could help mitigate BPD risk for children high in internalizing or externalizing symptoms. While past work in this field has focused mostly on risk, we take a more strengths-based approach and shift the focus to malleable factors that could be targeted with early intervention to prevent or ameliorate BPD development. Although future work would benefit from more valid measures, our method of using prospective data and multiple reports represents a strength of the current study that should be replicated if possible. In particular, observational measures may provide a more objective report as well as novel targets for screening. Further research is necessary to continue to parse out risk and protective factors in BPD development and to create interventions that might promote resilience and help prevent this debilitating disorder.Additional file 1. R Code for Multilevel Modeling Analyses. This document contains the R code used to perform the 12 multilevel modeling analyses conducted in the current study.


A 48-year-old male presented three days after cocaine use with acute, rapid onset of bilateral lower extremity weakness, bilateral foot numbness, acute urinary retention, and significantly elevated creatinine kinase. Further testing revealed unusual symmetrical edema with contrast enhancement on MRI of the lower extremities. The patient was diagnosed with severe non-traumatic, non-exertional rhabdomyolysis causing lumbosacral plexopathy following cocaine use. The treatment was centered around aggressive fluid resuscitation and electrolyte replacement. Rhabdomyolysis is a syndrome characterized by the rapid breakdown of striated skeletal muscle, which can occur as a complication of a multitude of inciting events . At firsA 48-year-old male with a past medical history significant for acquired hypothyroidism, compressive neuropathy of the ulnar nerve, rhabdomyolysis, and substance use disorder presented to our facility with rapid-onset, bilateral lower extremity weakness of less than 24-hour duration and three days post cocaine use. The weakness was associated with bilateral foot numbness, low back pain, urine retention, and inability to ambulate. The patient denied flu-like symptoms or diarrhea within the month preceding this hospital admission. There was no report or evidence of saddle anesthesia, urine or bowel incontinence, fever, or shortness of breath. Physical examination of the lower extremities was remarkable for grade 1/5 muscle strength and 1+ knee and ankle reflexes bilaterally. There was decreased sensation to the light touch of the feet bilaterally.Initial laboratory testing was remarkable for high creatinine kinase, myoglobin, and creatinine. Aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were also found to be elevated. The patient’s thyroid-stimulating hormone was high while the free T4 was low, indicative of medication non-compliance Table . Urine aA bedside ultrasound of the bladder after urination showed an abnormally distended bladder. Subsequently, a Foley catheter was inserted, which drained 1,500 cc of dark-colored urine. MRI of the lumbar spine with contrast was performed and showed a patent central canal and neuronal foramen with no focal disc herniation. However, it also detected abnormal posterior para-spinal, gluteal, and proximal thigh muscle signals, and enhancement without subcutaneous edema. Follow-up MRI of the pelvis and lower extremities with contrast was significant for an unusual symmetrical pattern of muscle edema with areas of contrast enhancement Figures . Lumbar The patient’s levothyroxine supplementation was restarted. He was aggressively hydrated with IV fluids, leading to a gradual decline in serum creatinine kinase and myoglobin. On the fifth day of admission, the patient showed significant clinical improvement in lower extremity motor strength and was able to lift both legs against gravity. A successful voiding trial was performed on the same day after which the Foley catheter was removed. The patient was able to walk with assistance on the sixth day of admission. Serum creatinine kinase levels dropped below 5,000 U/L on the ninth day of admission, and the patient was subsequently discharged to a rehabilitation facility.Rhabdomyolysis is a syndrome characterized by the rapid breakdown of striated skeletal muscle and the subsequent release of intracellular muscle constituents into the circulation . Its triThe lumbosacral plexus is a network of nerves formed by the anterior rami of the lumbar and sacral spinal cord . It inneAcute immune-mediated demyelinating polyneuropathy is a syndrome of neuronal demyelination secondary to an inciting event that triggers an immune response that cross-reacts with shared epitopes on peripheral nerves, a process called molecular mimicry . PatientIn an adult patient with rapid, bilateral lower extremity weakness and sensory deficits, and albumin-cytologic dissociation, MRI with contrast can be coupled with creatinine kinase levels to narrow the differentials down to severe rhabdomyolysis with lumbosacral plexopathy. Narrowing the differential down in this manner allows clinicians to administer specific treatments while avoiding unnecessary interventions such as IVIG. If evidence of hypothyroidism is detected, then concurrent thyroid replacement therapy should be administered.Rhabdomyolysis is a syndrome defined as the rapid breakdown of striated skeletal muscle that can be diagnosed through clinical and laboratory testing. However, due to its vast array of possible presentations and complications that are shared with multiple other syndromes, the decision to exclusively administer treatment for it can be difficult. MRI in rhabdomyolysis shows unusual symmetrical patterns of muscle edema with contrast enhancement. These MRI findings cannot be considered exclusive to rhabdomyolysis; however, when coupled with the clinical picture, they can serve to narrow down the differential diagnoses, assess the degree of muscle damage, raise suspicion for compressive neuropathy, and subsequently allow for a more accurate, safer, and cost-effective management plan.


Ralstonia and Pseudomonas were the top contributors to the neutrophil-associated resistome, whereas Campylobacter and Aggregatibacter contributed most to the eosinophil-associated resistome. Multiomic analyses revealed specific host pathways and inflammatory mediators associated with the resistome. The arachidonic acid metabolic pathway and matrix metallopeptidase 8 (MMP-8) exhibited the strongest associations with the neutrophil-associated resistome, whereas the eosinophil chemotaxis pathway and interleukin-13 (IL-13) showed the greatest associations with the eosinophil-associated resistome. These results highlight a previously unrecognized link between inflammation and the airway resistome and suggest the need for considering patient inflammatory subtype in decision-making about antibiotic use in COPD and broader chronic respiratory diseases.Antimicrobial resistance is a global concern in chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD). The collection of antibiotic resistance genes or resistome in human airways may underlie the resistance. COPD is heterogeneous, and understanding the airway resistome in relation to patient phenotype and endotype may inform precision antibiotic therapy. Here, we characterized the airway resistome for 94 COPD participants at stable disease. Among all demographic and clinical factors, patient inflammatory endotype was associated with the airway resistome. There were distinct resistome profiles between patients with neutrophilic or eosinophilic inflammation, two primary inflammatory endotypes in COPD. For neutrophil-predominant COPD, the resistome was dominated by multidrug resistance genes. For eosinophil-predominant COPD, the resistome was diverse, with an increased portion of patients showing a macrolide-high resistome. The differential antimicrobial resistance pattern was validated by sputum culture and IMPORTANCE Antibiotics are commonly prescribed for both acute and long-term prophylactic treatment in chronic airway disorders, such as chronic obstructive pulmonary disease (COPD), and the rapid growth of antibiotic resistance is alarming globally. The airway harbors a diverse collection of microorganisms known as microbiota, which serve as a reservoir for antibiotic resistance genes or the resistome. A comprehensive understanding of the airway resistome in relation to patient clinical and biological factors may help inform decisions to select appropriate antibiotics for clinical therapies. By deep multiomic profiling and in vitro phenotypic testing, we showed that inflammatory endotype, the underlying pattern of airway inflammation, was most strongly associated with the airway resistome in COPD patients. There were distinct resistome profiles between neutrophil-predominant and eosinophil-predominant COPD that were associated with different bacterial species, host pathways, and inflammatory markers, highlighting the need of considering patient inflammatory status in COPD antibiotic management. Chronic obstructive pulmonary disease (COPD) is one of the most prevalent respiratory diseases and is characterized by impaired lung function and persistent airway inflammation . COPD isn = 72) and Shenzhen People’s Hospital (n = 27) in China  and subjected to deep metagenomic sequencing (targeted >30 Gb of data per sample) with reagent controls . Among all demographic and clinical features, the inflammatory endotype had a statistically significant, albeit modest, association with the resistome . Eosinophil-associated ARGs were related to a diverse range of antibiotic classes, among which the macB and lnuA genes of MLS resistance were most significant (Table S4). Ralstonia spp. and Pseudomonas spp. were the top contributors to the neutrophil-associated ARGs, whereas species in Campylobacter and Aggregatibacter, previously found to be associated with sputum eosinophilia  . Genes iTaken together, these results uncover a previously unrecognized link between inflammatory endotype and the airway resistome in COPD. For neutrophilic-predominant COPD, the resistome was dominated by multidrug resistance genes from respiratory pathogens. For eosinophilic-predominant COPD, the resistome was diverse, with an increased portion of patients showing an MLS-high resistome. Our results suggest that the varied resistome across inflammatory endotypes could be a result of the underlying differences in the resident microbiota, whereas prior antibiotic history may be of less relevance, based on current data and literature , 8. ThesThe limitations of this study include its relatively small number of participants and cross-sectional nature. Despite having a validation cohort, the generalizability of the findings to patients with different demographic backgrounds and antibiotic history needs to be further assessed. In addition, it is important to assess the baseline resistome in healthy individuals in comparison with COPD patients. A previous study identified both shared and unique ARGs in healthy individuals and patients across a broad range of respiratory diseases, suggesting a complex airway resistome with both a core and discriminatory set of elements . Our resCNP0001954). The computer code has been deposited at https://github.com/wangzlab/COPD_Resistome.The raw multiomic sequencing data have been deposited in the Chinese National GenBank Nucleotide Sequence Archive (


The functions ascribed to eosinophils have classically been limited to host defence against certain parasitic infections and potentially deleterious effects in the setting of specific diseases that are associated with elevated eosinophil counts in blood and/or tissue. The ability to induce eosinophil depletion either experimentally in animal models or through targeted therapies in humans has extended our understanding of the roles played by eosinophils in health and homeostasis as well as in disease pathogenesis. When associated with human disease aetiology, the eosinophil takes on a pathogenic rather than a protective role. This maladaptive response, called “eosinophilic immune dysfunction” herein, appears central to exacerbation pathogenesis and disease control in severe asthma and may be involved in the aetiology of other eosinophil-related conditions ranging from organ-system-limited diseases such as phenotypic subsets of chronic obstructive pulmonary disease and chronic rhinosinusitis with nasal polyposis to more broadly systemic diseases such as eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. In this review, we describe the evidence supporting eosinophilic functions related to health and homeostasis and explore the contribution of eosinophilic immune dysfunction to human disease. The current era of therapies that specifically target eosinophils has yielded new insights into the functional significance of eosinophils in the maintenance of health and the effects of eosinophilic immune dysfunction on disease pathogenesis.https://bit.ly/3pVPLR5 In conjunction with the European Respiratory Society International Congress in 2020, an expert faculty participated in a sponsored symposium that described emerging evidence for the functional role of eosinophils in health maintenance and eosinophilic immune dysfunction as a contributor to disease pathogenesis across an array of inflammatory diseases. In this review, the presenters from the symposium revisit their original content and provide additional insights derived from the subsequent publication of relevant clinical trial data and analyses.e.g., benralizumab, mepolizumab, and reslizumab) will be presented.This is a fascinating time for scientists and clinicians interested in diseases that involve eosinophilic immune dysfunction, including severe asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), gastrointestinal diseases such as eosinophilic esophagitis (EoE), and systemic diseases such as eosinophilic granulomatosis with polyangiitis (EGPA) –4. Our uEosinophils are cells of the myeloid lineage that develop in the bone marrow in response to a specific combination of transcription factors and cytokines . Upon diEosinophils are granulocytes, and as such contain numerous granules of varying composition . CationiEosinophilic inflammation can be driven by T-cells, more specifically T helper type 2 (Th2) cells, which differentiate in response to dendritic cell presentation of certain antigens such as those derived from helminths or allergens . Th2 cele.g., cytokines, chemokines, lipid mediators) through the expression of a vast array of specific receptors . Th. Th59]. post hoc analysis of a phase 2b/3, placebo-controlled mepolizumab study performed by Ortegaet al. . Eo. Eo46]. termined .Eosinophils are found in a variety of skin diseases, including atopic dermatitis, contact dermatitis, eosinophilic cellulitis (Wells syndrome), bullous pemphigoid, and organ-restricted HES  45]. Th. Th45]. e.g., asthma non-responders, EGPA variants, COPD, CRSwNP), highlighting disease heterogeneity. For these conditions, endotyping will help identify patients who are likely to derive the greatest benefit from eosinophil-depleting/targeting therapies. Future studies that engage cross-disciplinary collaboration are key to recognising and understanding the role of eosinophils in health and disease.The findings presented here outline the importance of eosinophils in human disease, ranging from organ-system-limited diseases such as asthma and CRSwNP to more broadly systemic diseases such as EGPA and HES. The advent of eosinophil knockout animal models and eosinophil-targeted therapies in humans has enhanced our understanding of the roles played by eosinophils in disease and allowed the investigation of their possible involvement in health maintenance. Eosinophilic immune dysfunction appears central to exacerbation pathogenesis and disease control in severe asthma and is clearly involved in the aetiology of several other eosinophil-related conditions. There remain patient subsets in whom eosinophil depletion is insufficient to fully resolve disease manifestations (


Impaired sleep quality is among the most common complaints in psychopathological conditions including psychotic states. The clinical relevance of sleep disruption is, however, notoriously overlooked and considered as a secondary symptom that automatically ameliorates if the mental problem is adequately treated. Nevertheless, research findings indicate that sleep quality has a causal role in the occurrence and maintenance of psychotic states, and instead of being merely the “nocturnal impact” of an underlying mental disorder, shows bidirectional associations with mental health complaints.Although the majority of studies examined the links between sleep and psychosis by cross-sectional assessments, sleep quality and psychotic-like experiences both fluctuate from night to night and day to day, respectively, even in non-clinical populations. The prospective assessment of these variables hence allows for the analyses of the temporal  associations between sleep and psychosis. In our studies, we examined the temporal, bidirectional associations between sleep quality and psychotic-like states.Across three experience sampling studies with participants from the general population ( N = 73 / 166 / 60), we assessed sleep quality and daytime psychotic-like phenomena every day for at least two weeks. Using mixed-effects models, we examined if sleep quality predicted psychotic-like experiences the following day, and also if psychotic-like experiences predicted sleep quality the following night.Our findings consistently highlight the dominant direction of prediction from sleep to daytime psychotic-like experiences, whereas the inverse direction is not supported by enough evidence.Individuals at risk for psychosis could benefit from sleep-specific interventions that could be integrated into treatment protocols.No significant relationships.


JCI, Chen, Qiu, et al. used a reverse translation approach, isolating a Shigella sp. — peristaltic contraction–inhibiting bacterium (PIB) — from a cohort of patients with intractable constipation. They identified an ω-3 polyunsaturated fatty acid (PUFA), docosapentaenoic acid (DPA), produced by this Shigella variant, as an important driver of constipation using a series of microbiologic, biochemical, and genetic manipulations combined with in vitro and in vivo studies. This finding advances the field, given that production of DPA is rare in the human gut and appears to have a distinct effect on GI physiology.Gastrointestinal (GI) motility requires coordination among several cell types in the intestinal epithelium and the neuromuscular apparatus. A disruption in GI motility was primarily attributed to disruption of this coordinated effort among different host cells, but recent studies have begun to uncover how the products of gut microbiota can alter GI motility by modulating the function of different host cells and the interactions among them. In this issue of the  Chronic constipation is a common symptom with an overall median prevalence in adults of around 16% and a higher prevalence in women, adults over 60 years of age, and older adults who reside in institutions . An impoThe etiology of constipation is multifactorial, but recent studies have found a bidirectional interplay between GI transit and gut microbiota. Gut microbial metabolites alter GI transit, and changes in GI transit, in turn, are associated with alteration in gut microbiota composition and function. Furthermore, change in gut microbial function due to delayed GI transit promotes a feed-forward loop that further slows GI transit, highlighting the reciprocating reinforcement of pathophysiological host-microbe interaction . GI tranSeveral studies following the typical discovery-to-translation paradigm have identified microbiota-driven mechanisms that can alter GI transit. These studies utilized an array of preclinical models to determine the role of gut microbiota, such as using antibiotics to disrupt gut microbiota in conventionally raised mice, or comparing conventionally raised and germ-free (GF) mice. The specific effect of microbe(s) is often investigated by colonizing GF or antibiotic-treated mice with individual or a consortia of bacteria or human-derived gut bacteria. The findings from these models are combined with ex vivo , culture-based (primary cells or organoids), and omics-based studies to delineate the mechanisms driven by cellular components or metabolites of microbiota. These initial discoveries will need to be corroborated in humans before being developed as therapeutics .Key findings have emerged from such discovery-to-translation studies. A comparison of GF and conventionally raised mice found that gut microbiota are important for the maintenance of mucosal enteric glial cells . LPS, anJCI, Chen, Qiu, et al.  isolated from these patients inhibited spontaneous, but not stimulated, contraction in ex vivo mouse colon and jejunum segments. The authors identified docosapentaenoic acid  as the inhibitory metabolite produced by Shigella sp. PIB by separating the culture supernatant into polar and nonpolar phases followed by HPLC and LC-MS/MS. The inhibitory effect of DPA was verified in vitro and in vivo and further confirmed with a knockdown strain generated using a CRISPR interference system that targeted the ketoacyl synthase (KS) gene required for generating DPA. Mice colonized with the WT Shigella sp. PIB exhibited substantially longer GI transit time, reduced stool water, reduced frequency and amplitude of contraction in ex vivo colon segments, and reduced number of enteric glia when compared with noncolonized mice. Administration of strain-specific phages successfully eliminated the Shigella sp. PIB, reduced DPA levels in the stool, and accelerated GI transit time. Mice colonized with the KS knockdown strain  showed physiological activity similar to control mice, contrasting with the effects of the WT strain. These findings support a role for DPA in IFC. The authors extended these findings in a separate cohort to determine if the presence of the Shigella strain was restricted to IFC; they did not find this strain in the control groups   . A similnot IFC) .Shigella strain underlies the development of refractory constipation, will spur several lines of investigation. First, bacterial production of DPA is rare in the human gut and is predominantly a function of marine bacteria. It is intriguing to consider how these genes were acquired by this Shigella strain and if the associated function is prevalent in patients with refractory constipation across the globe. Second, while the authors found a decrease in enteric ganglia, the mechanism by which DPA exerts its effect on GI transit remains to be elucidated. The decrease in spontaneous contraction may be indicative of increased nitrergic neuronal signaling or of a loss of cholinergic neurons. Further, DPA may also affect the mucosa and submucosa; PUFAs have been found to exert biological effects on immune cells, adipocytes, and neuronal cells via GPR120 or GPR40 (The discovery by Chen, Qiu, et al., that DPA production by a or GPR40 , 20. Thior GPR40 ; Chen, Qor GPR40 . AlternaThe study by Chen, Qiu, et al.  supports


Cancer and cardiovascular disease remain leading causes of death and disability worldwide, which places a heavy burden on public health systems and causes widespread suffering. Because these entities have highly overlapping risk factors, including hyperlipidemia, hypertension, diabetes, obesity, smoking and other lifestyle factors, many studies have reported that they have similar etiological mechanisms. Accumulating evidence indicates that there is an increased risk of cardiovascular disease among cancer survivors compared with the general population. However, whether cancer is associated with an increased risk of cardiovascular disease remains controversial.We will conduct and report the meta-analysis strictly based on the Cochrane Handbook for Systematic Reviews and the Meta-analysis of Observational Studies in Epidemiology guidelines combined with the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols (PRISM-P). This meta-analysis was registered with PROSPERO (registration number CRD42022307056). We will search for studies published from database inception to December 1, 2021, regardless of language or date, in three electronic databases  to identify and appraise cohort studies examining the relationship between cancer and subsequent cardiovascular disease risk. The literature screening, inclusion and data extraction will be conducted independently by two investigators using pre-designed standardized data extraction forms. A senior investigator will be consulted in cases of disagreement. We will assess risk of bias in the included cohort studies using the Newcastle–Ottawa Scale (NOS). Quantitative synthesis will be conducted using a random-effects model. To explore potential sources of heterogeneity, we will carry out multiple sensitivity analysis, meta-regression and subgroup analysis according to baseline characteristics. Publication bias will be evaluated through visual inspection of funnel plot asymmetry as well as by Begg's rank correlation test and Egger's weighted linear regression test. Cancer and cardiovascular disease remain the leading causes of death and disability worldwide, which places a heavy burden on public health systems and causes widespread suffering –6. It haCancer and cardiovascular disease have highly overlapping risk factors, including hyperlipidemia, hypertension, diabetes, obesity, smoking and other lifestyle factors –15, and www.crd.york.ac.uk/prospero).We will conduct and report our meta-analysis strictly based on the Cochrane Handbook for Systematic Reviews and the Meta-analysis of Observational Studies in Epidemiology guidelines combined with the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols (PRISM-P)  Supplem. Details*/malignanc*/carcinoma AND cardiovascular diseases/coronary disease/stroke/myocardial infarction/myocardial ischemia/heart failure AND cohort study/longitudinal study/follow-up study/prospective study/retrospective study  or EMBASE Subject Heading (Emtree) terms along with free-text words that are associated with cancer and cardiovascular disease. The following search keywords and search logic will include cancer/tumor/tumor/oncology/neoplasmWe will include studies with the following inclusion criteria in qualitative analyses: (1) studies involving a prospective or retrospective population-based cohort; (2) participants diagnosed with cancer but no history of cardiovascular disease or not diagnosed with cardiovascular disease at the time of participant enrolment based on the International Classification of Diseases, Seventh to Tenth Revision (ICD 7–10) criteria in the population-based cohort and diagnosed with one type of cardiovascular disease during the subsequent follow-up period; (3) studies reporting risk estimates, including relative risk (RR), hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs), or studies that can provide relevant data to be used to estimate risk ratios. We will exclude hospital-based cohort studies and those with inadequate data to estimate risk ratios.Data extraction will be conducted independently by two investigators using pre-designed standardized data extraction forms and crosschecked by a third investigator. Disagreements will be resolved by consensus. The following study characteristics will be abstracted: first author, publication year and design, geographic region, observation period, participant age at cancer diagnosis, comparison population, criteria of diagnosis for cancer and cardiovascular disease, study findings and risk estimates of the association of cardiovascular disease with cancer.The risk of bias for the included studies will be assessed using the Newcastle–Ottawa scale (NOS) tool according to three major aspects: representativeness of the patients, ascertainment of exposure and outcomes and adequacy of follow-up . A totalI2 statistic will be employed to quantify the proportion of the total variation leading to heterogeneity, where an I2 > 50% indicates substantial heterogeneity . The summary RR among cancer survivors compared with that among the non-cancer population accompanied by its 95% CI will be defined as the primary outcome. Given the expected large heterogeneity for the participants, study design, and clinical and methodological aspects among the included studies, we will adopt the DerSimonian–Laird random-effects model to calculate risk estimates . RR willogeneity .post-hoc: study design, geographic regions, methodological quality, outcome division, age, sex, attained age, adjuvant therapy, cancer site and cardiovascular disease type. In addition, sensitivity analysis will be carried out by removing one study at each time and repeating the analysis to evaluate whether any individual study considerably influences the summary estimates. Meta-regression will also be performed to explain the effects of heterogeneity. We will explore the possibility of publication bias with visual inspection of a funnel plot and with Begg's rank correlation test and Egger's weighted linear regression test if 10 or more studies are included in the meta-analysis .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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Heart failure (HF) is a challenging situation in healthcare worldwide. Secondary mitral regurgitation (SMR) is a common condition in HF patients with reduced ejection fraction (HFrEF) and tends to be increasingly associated with unfavorable clinical outcomes as the severity of SMR increases. It is worth noting that SMR can deteriorate dynamically under stress. Over the past three decades, the characteristics of dynamic SMR have been studied. Dynamic SMR contributes to the reduction in exercise capacity and adverse clinical outcomes. Current guidelines refer to the indication of transcatheter edge-to-edge repair (TEER) for significant SMR based on data from the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial if symptomatic despite optimal guideline-directed medical therapy (GDMT) and cardiac resynchronization therapy (CRT), but nonpharmacological treatment for dynamic SMR remains challenging. In HFrEF patients with LV dyssynchrony and dynamic SMR, CRT can improve LV dyssynchrony and subsequently attenuate SMR at rest and during exercise. Also, a recent study suggests that TEER with GDMT and CRT is more effective in symptomatic patients with HFrEF and dynamic SMR than GDMT and CRT alone. Further studies are needed to evaluate the safety and efficacy of nonpharmacological treatments for dynamic SMR. In this review, current evidence and challenges for the future of dynamic SMR are discussed. Heart failure (HF) is a challenging situation in healthcare worldwide –3. HF wiIt is worth noting that SMR can deteriorate dynamically according to changes in hemodynamics . The chaThis review summarizes current evidence and challenges for the future of dynamic SMR in light of the mechanisms of dynamic SMR, its prognostic value, and its potentially effective treatment options.The mitral valve apparatus is intricately comprised of several components, including the mitral annulus, anterior and posterior mitral leaflets, chordae tendinae, anterolateral and posteromedial papillary muscles, and adjacent LV wall. MR can be regulated based on an exquisite balance among these components during systole. In SMR, tethering and closing forces of the mitral valve during systole are essential to understand the intricate mechanism. The tethering force is affected by LV dilatation, LV sphericity, LV regional wall motion abnormalities, papillary muscle displacement, papillary muscle dyssynchrony, papillary muscle asymmetry, annular dilatation, and annular flattening. The closing force is decreased due to LV contractility impairments, LV dyssynchrony, increased left atrial (LA) pressure, and decreased mitral annular contraction.Over the past three decades, the characteristics of dynamic SMR have been studied –13. Prev2 and VE/VCO2 slope and that the rate of exercise termination is higher in patients with dynamic SMR (ΔEROA ≥0.13 cm2 during exercise) than in those without dynamic SMR (2 during exercise) was less than that of patients without dynamic severe SMR  were shown to be unfavorable by Suzuki et al. /angiotensin II receptor blockers (ARB)/angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor agonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i); these drugs should be titrated to the maximum tolerated doses in all patients with HFrEF regardless of the presence of SMR –10. The A meta-analysis of three cardiac magnetic resonance imaging trials reported that SGLT2i therapy in patients with HFrEF was not significantly associated with reverse cardiac remodeling, including left ventricular ejection fraction, end-systolic volume, and end-diastolic volume; however, there was a tendency toward the improvement of these parameters .In HFrEF patients with persistent severe SMR, GDMT should be optimized as much as possible; however, such patients often suffer from either residual or worsening HF symptoms or undergo repeat HF hospitalization. Thus, when these patients have symptoms despite optimal GDMT, current guidelines recommend nonpharmacological treatment, including CRT and TEER (if applicable), after appropriate revascularization for significant coronary artery disease. However, there remains a matter for consideration in terms of nonpharmacological treatment for dynamic SMR in patients with HFrEF. Then, the nonpharmacological treatment of dynamic SMR is discussed below with a focus on CRT and TEER.In HFrEF patients with LV dyssynchrony, CRT can suppress LV dyssynchrony and subsequently improve LV hemodynamics while attenuating MR at rest and during exercise  20, 22), 2220, 2Also, it was (reportedly) possible to induce a left bundle branch block (LBBB) during exercise by increasing the heart rate of HFrEF patients with non-LBBB at rest . Rate-re2 during exercise) refractory to treatment with optimized GDMT and CRT if applicable (2) at rest but significant SMR (the EROA of 0.38 ± 0.10 cm2) during exercise, had a significantly higher rate of HF-related hospitalization and all-cause mortality than those in the TEER group. This suggested that resting SMR in patients with HFrEF is potentially underestimated unless ESE is performed and, consequently, even a non-significant resting SMR can bring about adverse clinical events if medically treated. In addition, this study addressed the association of EROA of SMR with left ventricular end-diastolic volume at rest and during exercise. In the study patients, EROA and left ventricular end-diastolic volume increased significantly during exercise, and as a result, the relationship between EROA in the study and left ventricular end-diastolic volume during exercise was similar to that in the COAPT study. Thus, ESE may be useful to figure out symptomatic patients with HFrEF who have potentially disproportionate dynamic SMR and are expected to receive adequate benefit from TEER.In patients with HFrEF and dynamic SMR, it may be possible that HF symptoms remain or recur with dynamic SMR refractory to optimal GDMT and CRT. In such patients, TEER can control not only the SMR at rest but also the dynamic change during exercise . Previouplicable . Of noteTEER can reduce the intensity of the symptoms of SMR and its prevalence because of the acute changes in mitral valve geometry as follows; improved coaptation area and mitral valve tethering, decreased anteroposterior diameter and area of the mitral annulus, and increased sphericity of the mitral annulus –50, all Optimal GDMT reduces the severity of SMR in patients with HFrEF , 35, 40.The study also reported that 67% of the patients who underwent TEER had either unchanged or uptitrated GDMT . Such paTEER for dynamic SMR may be expected to improve hemodynamics, mitral valve geometry, and HF symptoms, subsequently enabling patients to avoid downtitrated GDMT and gain clinical benefits as with TEER for persistent severe SMR. Thus, optimal GDMT even after TEER for dynamic SMR is also considered the crucial cornerstone of HF management considering its effect in further cardiac reverse remodeling and SMR reduction –53. FurtAlso, there are issues with ESE in patients with HFrEF and SMR; such patients can not exercise long enough to reach peak stress. Therefore, it may be difficult to compare dynamic SMRs among different patients based on certain stress criteria. Then, low-load ESE, which can be performed for a shorter time and under lower stress than conventional ESE, may be reasonable to evaluate the dynamic changes of SMR under specific stress in HFrEF patients. In such patients, it is expected that the usefulness of low load ESE will be examined in future.Dynamic SMR is associated with exercise performance impairments and adverse clinical outcomes in patients with HFrEF. In such patients, optimal GDMT and CRT are expected to ameliorate the deteriorated mitral valve apparatus, which subsequently leads to improvements in the dynamic SMR. Dynamic SMR can be residual or recurrent even after administering the appropriate treatments above. In such cases, other invasive treatment options, including TEER, may be indicated considering the effectiveness of TEER for dynamic SMR. CRT and TEER, along with GDMT, can improve deteriorated mitral valves and LVs, left ventricular dynamics, HF symptoms, exercise tolerance, and clinical outcomes. Even after obtaining such clinical benefits from CRT and TEER, GDMT regimens should be re-evaluated and reinforced as long as patients are tolerated to aim at further cardiac reverse remodeling and the reduction and prevention of dynamic SMR, subsequently leading to the amelioration of exercise tolerance and clinical outcomes.HO and MI drafted the manuscript and prepared the figures. TN, SN, and YA revised the manuscript. All authors read and approved the final manuscript.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pulmonary vein thrombosis (PVT) is an uncommon but often lethal disease with non-specific manifestations. Herein, we present a case of an elderly woman with a past medical history significant for limited-stage pelvic myxofibrosarcoma (MFS), who was admitted with subacute weakness and worsening dyspnea. Over the course of hospitalization, CT angiography was performed, which demonstrated a filling defect in the inferior left pulmonary vein consistent with PVT, in addition to evidence of widespread metastatic disease. The patient was offered therapeutic anticoagulation, but given the extent of her metastasis, the patient opted to transition to comfort care and pursued hospice care. This case serves as a unique presentation of a rare disease process associated with widespread metastatic MFS, illustrating the need for early recognition and treatment. Pulmonary vein thrombosis (PVT) is an uncommon but potentially lethal disease associated with a broad spectrum of conditions ranging from primary malignancy to radiofrequency ablation. This condition poses diagnostic challenges to clinicians due to non-specific presentations and the occasional need for multimodal imaging strategies for definitive diagnosis . While pA 71-year-old female with a past medical history significant for pelvic MFS status-post surgical debulking, hypertension, chronic obstructive pulmonary disease, and hypothyroidism presented to the emergency department complaining of a three-week history of generalized weakness and acutely worsening dyspnea.Two months prior to presentation, the patient was acutely diagnosed with high-grade MFS limited to the pelvis, for which she underwent resection of soft tissue sarcoma of the pelvis with subsequent pedicled transverse rectus abdominis myocutaneous flap to repair the right hip defect Figure . SurgicaThe patient then presented to the Emergency Department with vital signs notable for tachycardia with a heart rate of 107 bpm, hypertension with blood pressure of 150/72, and a new oxygen requirement of 4 L via nasal cannula. Physical examination was notable for decreased breath sounds bilaterally with mild bibasilar crackles, 1+ pitting edema bilaterally, and no notable calf tenderness.Initial serologic evaluation demonstrated mild leukocytosis WBC 11.3 K/uL), thrombocytosis (platelets 466 K/uL), and negative SARS-CoV-2 PCR. EKG demonstrated sinus tachycardia. Chest X-ray displayed multiple nodular-like opacities in bilateral lungs , transesophageal echocardiogram (TEE), ventilation-perfusion (VQ) imaging, and bronchoscopy offering some clinical benefit depending on the location of the thrombus and clinical presentation . As prevPVT in malignancy is a rare and life-threatening disease process only described in case reports without standard diagnostic or therapeutic recommendations given the lack of current data. Our case reinforces the need for further investigation into establishing a reliable diagnostic imaging modality, supporting the use of CT angiography in cases of known malignancy given the ability to identify parenchymal lesions that may be contributing to PVT. Furthermore, our case raises the question of a potential connection between different variants of sarcoma and PVT given an abnormally high ratio of case reports of sarcomatous malignancy and PVT. Finally, our case provides another unique data point to the large disparity in current literature, with the hope that compilation of case reports can eventually lead to standard diagnostic and therapeutic recommendations.


Differential diagnosis of brain lesion pathologies is complex, but it is nevertheless crucial for appropriate clinical management. Advanced imaging methods, including diffusion-weighted imaging and apparent diffusion coefficient, can help discriminate between brain mass lesions such as glioblastoma, brain metastasis, brain abscesses as well as brain lymphomas. These pathologies are characterized by blood-brain barrier alterations and have been extensively studied. However, the changes in the blood-brain barrier that are observed around brain pathologies and that contribute to the development of vasogenic brain edema are not well described. Some infiltrative brain pathologies such as glioblastoma are characterized by glioma cell infiltration in the brain tissue around the tumor mass and thus affect the nature of the vasogenic edema. Interestingly, a common feature of primary and secondary brain tumors or tumor-like brain lesions characterized by vasogenic brain edema is the formation of various molecules that lead to alterations of tight junctions and result in blood-brain barrier damage. The resulting vasogenic edema, especially blood-brain barrier disruption, can be visualized using advanced magnetic resonance imaging techniques, such as diffusion-weighted imaging and apparent diffusion coefficient. This review presents a comprehensive overview of blood-brain barrier changes contributing to the development of vasogenic brain edema around glioblastoma, brain metastases, lymphomas, and abscesses. This type of brain edema is dominant following brain ischemia and paucity of ATP. Subsequently, ionic or osmotic edema develops as a result of fluids and osmolytes redistribution between the extravascular and intravascular spaces. These differences lead to the water transfer into the brain parenchyma across the blood-brain barrier (BBB). Vasogenic edema results from the breakdown of BBB and typically occurs in the brain parenchyma surrounding nearly all malignant central nervous system (CNS) tumors, as well as brain abscesses  are formed by transmembrane glycoproteins, cadherins, cytoplasmic proteins, p120, and catenins α, β, and γ. These proteins are located on the basolateral cell membrane. Cadherins interact with the cytoskeleton of endothelial cells through catenins and p120, members of the Armadillo protein family . VasculaGap junctions (GJ) are specialized membrane protein structures between adjacent endothelial cells that contribute to maintaining TJ integrity and allow direct intercellular communication . GJ compThe basement membrane is a layer formed by a complex of extracellular matrix proteins and provides structural support for endothelial cells. The vascular basement membrane consists of a three-dimensional network and contains four major protein complexes made of laminins, collagen IV isoforms, heparan sulfate proteoglycans (perlecan), and nidogens. Collagen IV is the most abundant component of the basement membrane and interacts with endothelial cells and other basement membrane components . LamininPericytes are multifunctional cells with cytoplasmic processes attached to the basement membrane and surround the endothelial cells. Pericytes and endothelial cells are connected by different types of proteinaceous junctions such as TJ, GJ, and AJ . MoreoveAstrocytes are also an important component of the BBB. They are glial cells that interact with endothelial cells through their endfeet projections surrounding the abluminal side of capillaries. Astrocytes maintain homeostasis in the brain microenvironment, control neurotransmitter and ion concentrations, modulate synaptic transmission, and regulate immune reactions .GBM IDH-wild-type is the most common primary tumor of the CNS in adults and is characterized by rapid diffuse infiltrative growth of neoplastic glial cells, predominantly with astrocytic differentiation . Tumor cPrecipitative GBM growth necessitates a robust vascular system to supply the increasing nutrient and metabolic demands of the tumor mass. In contrast to the healthy brain vasculature with a highly organized physiological BBB, tumor vessels in GBM are remarkably irregular, structurally disorganized, and highly permeable, which results in irregular blood flow, vascular leakage, and brain edema. Morphologically GBM microvasculature might be divided into microvascular sprouting, which represents classic angiogenesis forming thin-walled capillaries, vascular mimicries, and bizarre vascular formations .Vascular mimicry, also called vasculogenic mimicry, is the uncanny ability of tumor cells to assume endothelial-like properties, including expression of junction proteins such as VE-cadherin, and form a network of channels independent of endothelial cells reminiscent of a capillary system . The tumThe neurovascular unit is a central component of the BBB that is dynamically modulated through tumor-neurovascular signaling. Glioma-induced BBB injury sequentially progresses to endothelial dysfunction followed by vasogenic edema. Subsequently, paracellular channels in the endothelium allow diffusion of plasmatic water molecules and proteins into the brain parenchyma, leading to characteristic peritumoral brain edema.The formation of vasogenic edema follows the structural disintegration of the endothelial BBB . AlteratSimilarly, down-regulation of claudin-1 and ZO-1 occurred through TGF-ß secretion, which is usually overexpressed in GBM . HoweverSeveral other mechanisms, including dysregulation in the expression of VEGF and aquaporins as well as pro-inflammatory changes, contribute to disruption in BBB and result in the development of vasogenic brain edema around GBM .Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) represent the main proangiogenic growth factors commonly involved in tumor neovascularization . DespiteSix VEGF isoforms have so far been identified, but it is the VEGF-A isoform that is most commonly implicated in the glioma-VEGF mediated signaling pathway . NeedlesAlternatively, VEGF can induce hyperpermeability by forming vesiculo-vacuolar organelles (VVO) and thus increasing endothelial transcellular transport . One of + channel SUR1-TRPM4 protein complex reverted astrocytic end-feet swelling  and disintegration of AQP4 into tetramers may be involved in determining the fate of glioma cells . GeneralThe role of the specific immune microenvironment in cancer pathogenesis has been extensively investigated in the past few years. These dynamic interactions between glioma tumor cells and immune cells in the tumor microenvironment were shown to influence glioma invasion, infiltration, angiogenesis, or peritumoral edema . Apart fBrain metastases are tumors primarily originating outside the CNS and spreading into the brain mainly through the hematogenous route or by direct infiltration from adjacent anatomic structures. Among those with the highest propensity to metastasize into the CNS are lung, breast, and renal cell carcinomas, along with melanomas. Brain metastases form solitary or multiple well-circumscribed masses with collateral brain edema .Disruption of BBB is considered one of the main causes of developing perilesional edema around brain metastases . SimilarVEGF action involves the synthesis and release of nitric oxide, activation of soluble guanylate cyclase and the consequent conversion of GTP to cGMP. This pathway of VEGF action contributes to BBB alteration and the development of peritumoral brain edema . The effVEGF has been found to cooperate with integrin αvβ5 and FAK and activate the Ras-ERK cascade. αvβ5 integrin expression was found on peritumoral vessels as well as on blood vessels in the surrounding brain parenchyma. On the other hand, increased expression of αvβ3 was found only on angiogenic, sprouting peritumoral vessels containing multilayered endothelial cells. Similarly, αvβ3, in collaboration with Basic Fibroblast Growth Factor (bFGF) receptor, activates downstream RAS and c-Raf, which leads to sustained Ras-ERK activation. These pathways regulate the expression of genes involved in cell survival, proliferation, differentiation, and migration . Moreove2+, which activates eNOS and, in turn, generates NO. The elevated level of intracellular calcium also stimulates the cytosolic phospholipase A (cPLA) and the production of prostaglandins. Vasoactive molecules, including NO and prostaglandins, lead to increased vascular cell permeability  and diacylglycerol (DAG). These molecules increase the intracellular concentration of Caeability . Other feability . This iseability . Unlike eability . In addieability . As parteability . Sulfonyeability . Moreovech edema , 2009.Reactive glial cells participate in NO-independent pathways that may be involved in the development of peritumoral brain edema around brain metastases. Cells such as microglia and astrocytes were found to contribute to an inflammatory response in these areas . ReactivThe microvascular density of brain metastases may influence the size of brain edema. High neovascularization and microvascular density were associated with large peritumoral edema . On the Glymphatic pathways may also play a role in the development of peritumoral edema. Recently, it was suggested that brain metastases may disrupt movement in the glymphatic pathways. Altered glymphatic pathways complicate interstitial fluid clearance and contribute to its accumulation in the tumor interstitium and peritumoral edema formation .The CNS might be affected by a wide range of hematological neoplasms, either primarily originating within the CNS or by secondary spread from lymphomas that produce systemic disease. Primary CNS lymphomas (PCNSL) are a type of extranodal non-Hodgkin’s lymphoma, accounting for less than 1% of non-Hodgkin’s lymphomas. Of these PCNSLs, diffuse large cell B-cell lymphoma of the CNS is the most common histologically defined tumor . PCNSL tA higher vascular permeability in PCNSL was detected by MRI imaging compared to GBM, which implies a greater degree of BBB disruption within the bulk tumor . This BBThe endothelial cell lining, originating from vascular progenitor cells or presumably even from tumor cells, is frequently flattened with fenestrations, or is discontinuous, exposing a duplicated or frayed basal membrane . InteresStaphylococcus aureus and Streptococcus species  in vasogenic edema in different brain lesions that can be detected and quantified by advanced MRI techniques such as ADC maps. These patterns can then contribute to improved diagnosis so that appropriate treatment may be applied for these brain pathologies.PS, MiH, and MB designed the study and wrote the manuscript. HV prepared the figures and participated in the preparation of the manuscript. MaH and RJ participated in the supervision and editing of the manuscript. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Intervertebral disc (IVD) degeneration is one of the major causes of lower back pain, a common health condition that greatly affects the quality of life. With an increasing elderly population and changes in lifestyle, there exists a high demand for novel treatment strategies for damaged IVDs. Researchers have investigated IVD tissue engineering (TE) as a way to restore biological and mechanical functions by regenerating or replacing damaged discs using scaffolds with suitable cells. These scaffolds can be constructed using material extrusion additive manufacturing (AM), a technique used to build three-dimensional (3D), custom discs utilising computer-aided design (CAD). Structural geometry can be controlled via the manipulation of printing parameters, material selection, temperature, and various other processing parameters. To date, there are no clinically relevant TE-IVDs available. In this review, advances in AM-based approaches for IVD TE are briefly discussed in order to achieve a better understanding of the requirements needed to obtain more effective, and ultimately clinically relevant, IVD TE constructs. Back pain statistics are stark; more than 80% of the adult population is affected by lower back pain, causing a huge socioeconomic burden, especially in developed countries ,2. FortyHealthy IVDs serve several purposes and are uniquely structured to perform them. They cushion the stacked vertebrae and so must be resistant to compressive load, but still be flexible enough to allow spinal movement. They must possess good viscoelastic properties and function reliably over a lifetime, To meet these demands, the IVD consists of three parts; an internal type II collagen and proteoglycan-rich compartment , a fibrous outer part  composed of repeating layers of type I and II collagen-rich sheets (lamellae), and the cartilaginous end plates (CEPs) that are bound to both the vertebrae and disc and control nutrient import , Figure Intervertebral disc degeneration (IVDD) is a broadly identified cause of back pain which exhibits increased proinflammatory activity and extracellular matrix (ECM) degradation leading to structural and biomechanical changes ,6,7. RisCurrent treatment regimens for IVD degeneration and associated lower back pain involve mostly conservative treatments, such as altering one’s lifestyle, rehabilitation and taking medication. More aggressive surgical treatments include spinal fusion, discectomy and total disc replacement ,11. SurgThe regenerative medicine approach, using tissue-engineering scaffolds for IVD replacement, if successful, would be superior to current treatment strategies by alleviating pain, allowing short-term repair and long-term tissue regeneration, decreasing immune rejection and re-herniation, as well as preserving disc height and restoring the natural range of motion ,16. OverThe field of regenerative medicine is vast—a Medline search results in over 95,000 hits—and excellent reviews on the topic abound ,18 with Here, we review additive manufacturing technologies used for IVD tissue engineering, with a focus on the replacement of the damaged IVD as a whole.Additive manufacturing, also known as rapid prototyping or solid free-form technique, forms 3D objects in a layer-by-layer manner to produce a three-dimensional structure based on computer-aided design (CAD) data ,21. SomeMore and more research facilities have started utilising additive manufacturing technologies for tissue engineering purposes. IVD tissue engineering is not an exception. The technique is highly advantageous to produce personalised IVD scaffolds, as IVD shapes are unique between individuals and IVDs have a highly complex architecture. In addition, rapid prototyping can integrate with imaging techniques, such as computed tomography scanning, to create scaffolds with a customised structure.Although currently, a majority of the IVD tissue engineering studies utilise polymer electrospinning or hydrogel moulding, some of them have employed additive manufacturing technologies . ComposiThree-dimensional printing is an extrusion-based, additive manufacturing technique that extrudes ink/bioink through a nozzle in a layer-by-layer manner to create 3D structure. It includes FDM and 3D bioprinting, which employ different ways of preparing ink  for extrusion .FDM is used in tissue engineering due to its affordability and ease of scaffold manufacturing . Unlike For tissue engineering the whole IVD, FDM is also commonly used, mainly to provide mechanical strength to withstand the physical loads that are expected to be applied to the IVD scaffolds. The biomaterials used in this field are PCL, PLA, and FlexiFil PLA (FPLA) filaments ,28,29,303D bioprinting is a type of 3D printing which uses hydrogels that encapsulate cells as a bioink. The printed scaffold is typically cured/crosslinked using UV light or other chemicals after the printing is complete. Similar to FDM and other extrusion-based 3D printing, the bioink is extruded through a nozzle and deposited onto a platform that typically, is cooled . Some ofSeveral studies bioprinted cell-laden hydrogels such as alginate, gellan gum–poly (ethylene glycol) diacrylate (GG–PEGDA), and gelatin–hyaluronic acid–sodium alginate seeded with chondrocytes and bone marrow stromal cells ,26,29,30Melt electrowriting is a newly emerging technique, that combines the best of both worlds of 3D printing and electrospinning. It deposits electrically controlled fine microfibres onto the platform to fabricate precise layer-by-layer scaffolds. The main feature of MEW is that it uses heat-molten biomaterials, but with much finer strands deposited compared to FDM. MEW also allows control over the microarchitecture of the scaffold unlike electrospinning . This isDespite the gross anatomy of the IVD appearing simple, reproduction of the complex microstructure has proven to be challenging . While nOne of the main issues with IVD tissue engineering is that the rate of IVD regeneration is extremely slow . This imDeveloping scaffolds which mimic the microstructure of the native IVD is a good way to ensure that the ECM deposited is similarly aligned to that of native IVDs. This also encourages cells in the AF region to elongate in the appropriate direction, mimicking the native IVD environment. Jungst et al. reported that the differentiation of MSCs can be directed with MEW scaffold design, which suggests that additive manufacturing, in particular MEW, may provide great advantages in creating AF scaffold which mimics the native AF microstructure . AnotherIt is known that spinal fusion or total IVD arthroplasty can cause adjacent segment disease, a condition where the IVDs above or below the fused vertebrae degenerate post-surgery . One of Although there are other studies that performed “close-to-human” in vivo experiments for IVD constructs with large animals ,51, to tThe IVD structure is the largest avascular structure in the human body. Therefore, it is prone to suffer from a lack of nutrients and cell diffusion throughout its scaffold . HoweverSome studies reported the loss of proteoglycans from IVD scaffolds to culture medium in the in vitro environment during the 60 days of culture . This loIn recent years, there have been several studies exploring whole IVD tissue engineering using additive manufacturing. However, there are still several challenges to developing functional IVD constructs that have an optimal balance between the required structural, mechanical and biological properties. Due to the capability of fabricating patient-specific implants and easily customisable scaffolds, additive manufacturing technology is expected to gather more research interest in the field of tissue engineering. The addition of biomimetic CEP might resolve some of the issues associated with IVD tissue engineering. Further development and investigation of fabrication methods, biomaterials and cells are required for the future 3D success of IVD tissue engineering.