JCI, Arinze et al. explore the role of tryptophan metabolites in chronic kidney disease–associated (CKD-associated) peripheral arterial disease. The authors used mouse and zebrafish models to show that circulating indoxyl sulfate (IS) blocked endothelial Wnt signaling, which impaired angiogenesis. Plasma levels of IS and other tryptophan metabolites correlated with adverse peripheral vascular disease events in humans. These findings suggest that lowering IS may benefit individuals with CKD and ESKD.Patients with end-stage kidney disease (ESKD) have increased vascular disease. While protein-bound molecules that escape hemodialysis may contribute to uremic toxicity, specific contributing toxins remain ambiguous. In this issue of the  The use of chronic dialysis in patients with end-stage kidney disease (ESKD) is one of the miracles of modern medicine with which we can keep patients with kidney failure alive; however, dialysis does not completely remove the many uremic toxins . PatientJCI, Arinze et al. provide in vivo evidence in mouse and zebrafish animal models that circulating IS (at concentrations found in humans with CKD) blocks Wnt signaling in the endothelium and impairs angiogenesis in a Wnt ligand–independent fashion  . The autWhile the in vivo findings compellingly link IS with PAD, several questions remain unanswered. The hind-limb ischemia model is a comparatively acute model focusing on capillary bed density that may only reflect part of the pathophysiology of PAD associated with CKD. Although increased concentrations of IS have been associated with PAD in hemodialysis patients, IS does not seem to have any substantial association with other cardiovascular outcomes . ConsequTaken together with other published studies, Arinze’s study shows that activation of AhR by IS and other tryptophan metabolites is now implicated in multiple pathophysiologic processes associated with CKD, including glomerular injury, renal fibrosis, atherogenesis and cardiovascular disease, protein energy wasting, renal anemia, loss of bone mineralization, and cognitive dysfunction . Finding


A 93-year-old man living in a nursing home presented to our emergency department with altered mental status. Examination revealed hypotension and severe hypoxia. Chest radiograph showed infiltrates in the right upper lobe, and computed tomography of the abdomen and pelvis demonstrated a left femoral neck fracture. A point-of-care transthoracic echocardiogram (TTE) revealed an enlarged right ventricle, severe tricuspid regurgitation, and numerous white floating dots moving toward the right atrium from the inferior vena cava (IVC), leading to the diagnosis of fat embolism syndrome (FES).Although imaging studies can facilitate diagnosis, the diagnosis of FES is typically made by clinical history and presentation, making a swift diagnosis often difficult in those who are critically ill. Recent case reports have described that TTE can detect fat emboli, seen as flowing hyperechoic particles in IVC. This image demonstrates the utility of TTE to diagnose FES. A 93-year-old man living in a nursing home presented to our emergency department with altered mental status, which occurred suddenly over the previous one hour. An initial history elicited from the nursing home staff failed to identify any risk factors. Examination revealed hypotension and severe hypoxia with oxygen saturation of 85% on 15 liters per minute oxygen with a non-rebreather mask. Chest radiograph showed infiltrates in the right upper lobe, but contrast computed tomography (CT) showed no pulmonary embolism. Suspecting an occult organ pathology, we ordered CT of the abdomen and pelvis, which demonstrated a left femoral neck fracture. Further inquiry of the nursing home staff revealed that the patient had fallen earlier on the same day, striking his hip on the floor. A point-of-care transthoracic echocardiogram (TTE) revealed an enlarged right ventricle, severe tricuspid regurgitation, and numerous white floating dots moving toward the right atrium from the inferior vena cava (IVC) , leadingFat embolism syndrome is a rare condition defined by the presence of fat globules in respiratory circulation.What do we already know about this clinical entity?Fat embolism syndrome (FES) is defined by the presence of fat globules in respiratory circulation; its diagnosis is often challenging.What is the major impact of the image(s)?Floating fat emboli can be detected using point-of-care ultrasound, which facilitates the diagnosis of FES.How might this improve emergency medicine practice?Point-of-care transthoracic ultrasound is an essential diagnostic tool to evaluate patients with suspected FES.VideoTransthoracic echocardiogram. The video shows numerous white floating dots moving toward the right atrium (RA) from the inferior vena cava (IVC) suggestive of fat embolism syndrome.


Delivery of serious illness communication (SIC) is necessary to ensure that all seriously ill patients receive goal-concordant care. However, the current SIC delivery process contains barriers that prevent the delivery of timely and effective SIC. In this paper, we describe the current bottlenecks of the traditional SIC workflow and explore how a hybrid artificial intelligence-human workflow may improve the efficiency and effectiveness of SIC delivery in busy practice settings. High-quality and timely SIC enables and enhances decision-making and care planning through the process of cultivating patients’ prognostic awareness and translating their values and priorities into patient-centered recommendations. The iterative and non-linear process of SIC requires frequent and early conversations to ensure that clinicians accurately understand patients’ evolving goals, values, and priorities and to make patient-centered recommendations throughout the illness trajectory.Serious illness communication (SIC) is an essential component of palliative care that ensures the delivery of goal-concordant care. SIC is often defined as the conversations between clinicians and patients with serious illness about their goals, values, and prioritiesThe traditional SIC delivery process consists of a series of conversations where gathering, interpreting, and integrating SIC data occur within a clinical encounter followed by manual clinician documentation in the electronic health record (EHR) post-visit. This process can be broken down into the following steps: determining patient eligibility for SIC; gathering and interpreting information ; conducting a therapeutic conversation  with the goal of shared decision-making; documenting the conversation; and making SIC documentation accessible to others in the EHR Fig. . However2. Second, patients and/or clinicians may be unclear about the optimal timing and when to make such conversations a priority2. Third, clinicians often lack time to conduct SIC2 and to document these conversations adequately3. Fourth, standards for EHRs to facilitate consistent, accurate documentation that is easily accessible to all care team members are lacking4. Therefore, in addition to training more clinicians to be competent in SIC, a novel workflow that addresses these barriers will be necessary to ensure that all seriously ill patients receive timely and effective SIC that informs their care in real time and naturally results in documentation of patients’ goals and preferences that is visible to others. We propose that a hybrid artificial intelligence (AI)-human workflow can improve this process by helping clinicians identify patients with SIC needs more accurately; promoting upstream data collection to facilitate more efficient in-person shared decision-making; reducing clinician documentation burden by streamlining the SIC documentation process; facilitating seamless sharing of patient goals and preferences via accurate and efficient identification of SIC documentation in the EHR; and providing real-time feedback to clinicians on their SIC skills.First, most clinicians lack SIC training and feel unprepared to have these difficult conversations with their patients5. Moreover, systematic methods to identify patients with palliative care needs are lacking6. To solve this problem, AI researchers have developed machine learning algorithms to generate more accurate mortality predictions to facilitate earlier SIC and palliative care delivery8. Some researchers have demonstrated that coupling AI-generated mortality predictions with behavioral nudges to clinicians can improve SIC frequency9. However, critics have expressed worry about using mortality predictions alone for identifying populations with palliative care needs because a reductionistic interpretation of these results may lead to further propagation of algorithmic or other systemic biases leading to inequitable care and patient harm10. Therefore, others have suggested alternative metrics that identify patients at risk of worsening serious illness to train predictive algorithms—including functional decline, deteriorating quality of life, escalating caregiver burden, or psychosocial or spiritual distress10. Some accountable care organizations are already using claims-based algorithms to identify high-cost patients who would benefit from earlier palliative care11, but greater effort is needed to mitigate algorithmic bias, especially among commercially available products that are widely used12. Moreover, additional methods to identify SIC-eligible patients should be considered since EHR-based algorithms often have performance gaps13.Patients with serious illness often experience delayed SIC because clinicians are poor at prognosticating life expectancy for terminally ill patients, usually erring on the side of optimism16, but the technology to date is mature enough to support its use in SIC as a basic data-gathering agent. One could imagine SIC conversational agents that would collect information about the patient’s prognostic awareness and priorities prior to in-person visits. Doing so would enable clinicians to maximize face-to-face time on higher-order cognitive and emotional tasks  that would lead to earlier shared decision-making. Conversational agents may also give patients time to reflect and discuss issues with trusted persons prior to meeting with the clinician.The use of conversational agents (aka chatbots) has largely been unexplored in palliative care. Conversational agents that are emotionally aware or use unconstrained natural language input are nascent in health care18. In one study, older adults utilized multiple-choice responses to converse with an agent that provided spiritual counseling, which reduced anxiety and increased the intent to create a last will and testament17. In another, machine learning algorithms allowed the agent to collect patient-reported outcome measures and display empathy to the users’ free text responses18. Although conversational agents were well-received in these preliminary studies, some patients will prefer to have the entire SIC with their clinicians directly, obviating the need for a chatbot. Further studies need to be conducted on actual patients with serious illness and should assess if conversational agent-led SIC triggers emotional distress in patients or actually enhances the patient-clinician relationship. Moreover, deploying conversational agents may inadvertently widen inequities in certain populations, particularly patients with limited English proficiency, health information technology literacy, or broadband access.To date, no studies on conversational agents have been conducted on patients with serious illness, but proof-of-concept studies in the general population have demonstrated the acceptability of conversational agents that address palliative care-related topics3. NLP-enabled dictation software has demonstrated the ability to reduce medical documentation time while maintaining documentation quality19 and is already commercially available20. Such technology would reduce the time clinicians spend manually writing notes and minimize recall bias since the content of the conversation is transcribed verbatim during the conversation and not hours later, typical of much documentation. As a result, nuanced details of the conversation are readily captured in real time leading to higher quality notes with less clinician effort.AI can also streamline the SIC documentation process and potentially improve the quality of SIC documentation via natural language processing (NLP)—a form of machine learning designed to understand, interpret, or manipulate human language. Missing or incomplete documentation in the EHR regarding patient preferences for life-sustaining treatment is common and contributes to medical errors related to end-of-life care4. In its current state, identifying SIC documentation in the EHR typically involves a manual chart review that possibly includes a keyword search or utilization of note filters. NLP-enabled software that identifies free text SIC documentation would likely reduce the time and effort clinicians spend looking for this information and prevent inadvertent oversight of patient preferences leading to goal-discordant care. AI-assisted chart reviews have demonstrated higher accuracy and shorter time for extracting relevant patient information compared with standard chart reviews21. Additionally, NLP has demonstrated the ability to identify SIC documentation accurately from EHR data and, in some cases, more accurately than human coders24. However, the accuracy of NLP to identify SIC documentation largely depends on the quality of the gold standard dataset created by human annotation used to train the model. Consequently, widespread implementation of NLP-enabled software to identify SIC documentation likely remain years away since high-quality annotated examples to train generalizable models are lacking, and adapting NLP models between different datasets often require additional training or fine-tuning25. In the interim, some health systems have created a centralized location for SIC documentation in the EHR to improve SIC documentation identification26, but compliance with utilizing these modules will likely remain an issue and additional NLP assistance will optimize the identification of SIC documentation in the EHR27.NLP also has the potential to address barriers resulting from poor EHR design that prevent or inhibit the extraction and flow of meaningful advanced care planning information across the care continuum28. Automated speech analysis and communication feedback will likely take years to manifest because not only do technical and logistical barriers remain 28, but also greater consensus is needed to define and measure basic communication quality and outcomes29. Researchers are currently utilizing NLP to analyze audio recordings of SIC to characterize and understand the naturally occurring features of these complex conversations32, such as identifying intentional pauses that foster empathy, compassion, and understanding, aka “Connectional Silences.30" This type of research will guide future efforts to develop ways of automating the measurement of SIC quality in real time, allowing for immediate feedback to improve clinician performance.Finally, AI has the potential to improve SIC delivery by providing speech analysis and personalized feedback to clinicians regarding their communication skillsIn conclusion, a hybrid AI-human SIC workflow may improve the efficiency and effectiveness of SIC delivery in busy practice settings. Some of the AI technology are available for widespread use presently , whereas others are emerging technologies that are being developed and studied . This proposed paradigm still requires that clinicians undergo some SIC training to capitalize on the assistance provided by AI, as well as additional research to avoid unintended consequences of AI implementation. That said, a semi-automated approach to SIC delivery holds tremendous promise and would likely improve current SIC workflow by optimizing clinical manpower and efficiency while increasing the likelihood that these critically important conversations will occur effectively and in a timely fashion.


Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol’s effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol’s effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood. This rsee . The devsee (see ). One resee  . Ethanol exposure exerts adverse consequences on the brain throughout the lifespan, with deficits evident from exposure during perinatal development through adulthood. The spectrum of ethanol’s adverse effects produces enormous individual, interpersonal, and societal costs. For example, the robust teratogenic effects of ethanol exposure egnancy)  makes feegnancy) . Of noteegnancy) . Furtheregnancy) . The preegnancy) . Howeverncy) see.Each section of this review will discuss the adult impact of ethanol exposure on these systems during discrete neurodevelopmental windows: perinatal, adolescence, and adulthood. Incubation effects, persistence, and reversibility will be discussed, with sex differences highlighted when applicable. The goal of this review is to highlight the molecular underpinnings of ethanol’s impact on hippocampal neurogenesis across the continuum of the lifespan.in utero and neonatal) development induce long-lasting neurodevelopmental consequences on neurological structure and function due to alterations in development of neurocircuitry and other neurobiological systems, permanently shifting maturational trajectories in both the brain and body. One of the most ubiquitously known teratogens is ethanol, and the consequences of ethanol exposure during perinatal development are devastating. These consequences were first documented in 1968 by Paul Lemoine , therebirth see.see . In addThe myriad of developmental and pharmacological variations in rodent FASD models complicates translation of findings to the human literature, particularly when results vary by experimental design. For example, the characteristic facial dysmorphology evidenced in children with FASD  has been specifically linked to ethanol-induced cell death during early embryonic exposure (mouse embryonic days 7–9)  are not see , findinsee see. Althougsee see. As suchsee see. The lacseeHuman studies of FASD indicate prior alcohol exposure results in attenuated age-related increases in hippocampal volume across adolescent development . HoweverseeFuture studies will need to elaborate on these findings, particularly in relation to perinatal ethanol-driven effects on adult hippocampal neurogenesis versus gliogenesis as well as potential sensitivity differences in males versus females. Examination and reporting of both sexes is particularly critical, as some studies have found differences solely in one sex but not the other see. For exaseeThe cholinergic system rapidly develops during the early neonatal period in rodents see, and is 1) ethanol-induced decreases in adult basal forebrain cholinergic neurons may result from caspase-3-mediated apoptotic cell death during critical neonatal developmental windows, and 2) reductions in adult populations of basal forebrain cholinergic neurons after neonatal ethanol exposure do not recover despite long periods of abstinence. These findings have been reproduced across a variety of mammalian species, from mice to primates, suggesting a high level of congruency in this literature. Moreover, neonatal ethanol-induced loss of basal forebrain cholinergic neurons is accompanied by diminished evoked acetylcholine efflux in the adult hippocampus as assessed using in vivo microdialysis, indicating that perinatal ethanol exposure persistently disrupts basal forebrain-hippocampal cholinergic neurocircuitry  the critical role of acetylcholine in neurogenesis, 2) the likely contribution of acetylcholine reductions to loss of neurogenesis in these model, and 3) the therapeutic potential of compounds which target the cholinergic system in FASD.Loss of basal forebrain cholinergic neurons and subsequent diminution of acetylcholine efflux in the hippocampus have critical implications for cognitive and behavioral deficits in FASD and preclinical models of FASD. For example, deprivation of choline, which is an essential nutrient and critical component of acetylcholine synthesis, exacerbates perinatal ethanol-induced deficits in motor development in early life . Conversult rats . This suult rats , furtherOne of the mechanisms by which perinatal ethanol-induced disruption of basal forebrain-hippocampal cholinergic neurocircuitry may affect adult hippocampal neurogenesis is through long-term alterations in cholinergic receptor activation in adulthood. Both muscarinic and nicotinic receptors directly affect neuroprogenitor pools and indirectly regulate the hippocampal environmental milieu. Muscarinic M1 receptors are abundant in the adult hippocampus, where they colocalize with newborn cells in the dentate gyrus to play a key role in hippocampal cell proliferation . In factInterestingly, the sole study reporting that ethanol exposure across gestation decreases adult cell proliferation  parallelIn contrast to muscarinic receptors, nicotinic receptors have received little attention in relation to the lasting effects of perinatal ethanol exposure, with a single study reporting that hippocampal α7 nicotinic receptor density in adulthood is unaffected by perinatal  ethanol exposure . Howeversee . While see . Microglsee . Interessee . Future Specifically, prenatal ethanol exposure increased CCL6, IL-21, IL-10ra, and TNFα expression in the developing brain of male and female rats, relative to age-matched controls, on E17 , with feThe effects of perinatal ethanol on innate immune activation are further exacerbated in adulthood. This is in part due to the fact that perinatal ethanol has cascading repercussions on immune regulation of the developing cholinergic system to impact later neuroimmune signaling dynamics in adulthood. For example, some studies suggest perinatal ethanol sensitizes later innate immune gene responses in adulthood, in part due to diminished capacity for cholinergic anti-inflammatory feedback that leads to an exaggerated proinflammatory neuroimmune response. Prenatal ethanol exposure  dramatically exacerbates the adult response to modest innate immune challenges (25 μg/kg lipopolysaccharide [LPS]), evidenced by exaggerated hippocampal gene expression of IL-1β and IL-6 in male rats but not female rats, relative to controls . SimilarIn addition, persistent increases in CCL2 signaling  by perinseeCollectively, these findings indicate that perinatal ethanol-induced acute induction of proinflammatory signaling cascades may be an early underlying factor in developmental cholinergic deficits by contributing to their programmed cell death during rodent neonatal or human third-trimester development. In adulthood, these developmental deficits in cholinergic function may unmask greater impairments under conditions of neuronal stress, potentially through alterations in muscarinic and nicotinic receptor activation and consequential augmented disruption of the proinflammatory signaling in the hippocampal environmental milieu, reflecting a vicious cycle that may drive both impairments in neurogenesis and greater cognitive deficits in high-complexity tasks see.1) ethanol-induced alterations during perinatal development persistently impact development by changing gene transcription, 2) some consequences of perinatal ethanol will emerge over time in conjunction with developmental changes in epigenetic regulation of gene expression, and 3) pharmacological interventions which aim to reverse perinatal ethanol-induced developmental effects will be most effective if they also reverse perinatal ethanol-induced epigenetic changes.Children with FASD have several complications due to large-scale cell death induced by prenatal alcohol exposure coupled with broad shifts in epigenetic regulation of gene expression. Epigenetics is the modulation of gene expression in the absence of alterations to DNA, making it a master director of brain development by altering gene accessibility to transcriptional machinery across time . For exaThe emergence of ethanol’s cascading consequences on neurodevelopment over time complicates interventions aimed at reversal of neurological and behavioral deficits in models of FASD. In fact, the majority of current pharmacological intervention strategies approved for children with FASD target other neuropsychiatric comorbidities, such as the use of stimulants for the highly co-morbid diagnosis of attention deficit hyperactivity disorder in FASD children, with few treatment strategies aimed to prevent or reverse FASD pathophysiology itself . These cThe positive preclinical effects of choline supplementation on FASD behavioral and neurological outcomes have given it a spotlight in clinical trials, several of which are ongoing . HoweverAdolescence is a period of rapid brain maturation with extensive myelination, synaptic pruning, and neurogenesis, highlighting that remodeling of molecular circuitry is a critical component of this developmental period that parallels rapid behavioral and cognitive growth . Adolesc1) National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), which evaluates the progressive disruption of neurodevelopment and behavioral alterations with alcohol exposure across adolescence in humans, and 2) the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium, which uses rodent models of adolescent intermittent binge ethanol exposure to examine mechanisms underlying ethanol’s long-term molecular and cognitive-behavioral changes in adulthood (via an intermittent dosing regimen that results in the high BECs (>150 mg/dl) that are achieved in human adolescents . Findinnts (see ). This sNeurogenesis during adolescent development is on average four-fold greater than during early adulthood , and thisee  a failure to assimilate signals driving successful integration into existing hippocampal circuitry or 2) hypersensitivity to the stimulation of cell death executioner pathways.The enduring loss of hippocampal newborn neurons after AIE most likely involves both subtle disruptions in the neuroprogenitor cell proliferating pool as well as more robust findings involving decreased survival of neuroprogenitors as they differentiate into neurons and integrate into hippocampal circuitry  expression of pNF-κB p65 . This phAdolescent binge ethanol exposure causes a loss of basal forebrain cholinergic neurons immediately following the conclusion of ethanol treatment  that persists well into adulthood , paralleling AIE-induced lasting reductions in hippocampal neurogenesis and proinflammatory induction. The observed 20–30% reduction in basal forebrain cholinergic neuron number following adolescent binge ethanol exposure is consistent across both mouse and rat studies  in both 1) concurrent induction of caspase activity of these neurons during critical neurodevelopmental windows during the brain’s growth spurt, and 2) failure to restore ChAT immunoreactivity with pharmacological or environmental interventions . In parorebrain . Similarorebrain .Both HMGB1 and phosphorylation of NFκB p65/p50 have been implicated in pathways that modify epigenetic machinery, although their roles are complex, depending in part on co-activation of other factors. Thus, HMGB1 and NFκB p65/p50 can have distinct functions under normal physiological versus pathological conditions. For example, under normal physiological developmental conditions, nuclear HMGB1 promotes the formation of transcription complexes by overcoming limitations with tightly bent DNA . In contseeEthanol-induced epigenetic silencing shines light on potential mechanisms for recovery with interventions that reverse this epigenetic silencing , and in Despite the loss of basal forebrain cholinergic neuron phenotype, behaviorally-evoked acetylcholine in the hippocampus during reversal learning in adulthood is slightly, but non-significantly, blunted by prior adolescent binge ethanol exposure . This fivia decreased nAChRα7 activation on immunocompetent glia is at the juncture of both persistent inductions in neuroinflammatory signaling cascades, induction of apoptotic executioner caspases, and reductions in survival of adult newborn neurons.Adolescent brain maturation shows developmental reductions in nicotinic cholinergic receptor expression . InteresseeAIE persistent induction of neuroimmune genes as well as reduction in hippocampal neurogenesis corresponds with impairments in a variety of learning and memory tasks, including discrimination learning  and reveDuring the adolescent developmental period, changes are governed by alterations in epigenetic regulation of cholinergic and neuroimmune genes, driving an environmental imbalance in the hippocampal environmental milieu which is unfavorable to the successful adult birth, maturation, and integration of newborn hippocampal neurons. This suggests that in the absence of intervention, both adolescent ethanol-induced loss of neurogenesis , basal fAlcohol use disorder (AUD) is highly prevalent in Western society, with estimates of up to 29% of adults suffering from AUD at some point in their lifetime . This disee , rodentsee . CollectPreclinical studies indicate that adult chronic binge ethanol exposure decreases hippocampal neuroprogenitor cell proliferation and neurogenesis  even in seeAdult ethanol-induced suppression of hippocampal cell proliferation is further complicated by withdrawal periods, as there is some evidence for a brief burst in cell proliferation 1 week into abstinence . Howeverin vivo microdialysis studies in adults after long-term 3-month ethanol exposure in drinking water, acetylcholine efflux in the hippocampus was significantly reduced by 57%, relative to controls (The basal forebrain cholinergic system is profoundly affected by ethanol during early development, with both perinatal and AIE exposure reducing basal forebrain cholinergic neuron expression in addition to decreasing cholinergic regulation of the hippocampus. However, adult alcohol exposure does not produce as rapid or robust an effect on the basal forebrain cholinergic system. Just as intermittent ethanol exposure across adolescence but not adulthood produces deficits in adult hippocampal neurogenesis , adolesccontrols . This efChronic ethanol exposure in adulthood can also disrupt cholinergic receptors, but this finding is complex and largely depends on subtype. For example, 10 weeks of ethanol consumption decreases hippocampal nicotinic receptor expression independently from altering binding affinity . In contThe loss of hippocampal nicotinic receptor expression could underlie sensitivity to neuroinflammatory induction after chronic ethanol in adulthood, as microglial nicotinic α7 receptors play critical negative feedback role for proinflammatory cascades. Thus, loss of activation at nicotinic α7 receptors is suggestive of a loss of anti-inflammatory feedback and chronic induction of proinflammatory signaling cascades in the brain of individuals with AUD. In support of this concept, an increase in neuroinflammation in post-mortem human brains with AUD is one of the most prevalent clinical findings , and prephox NADPH oxidase subunit, TNFα, and IL-1β as well as greater morphological changes in microglia (The effect of ethanol on hippocampal neuroinflammation can be magnified under conditions which challenge the immune system, such as a LPS or polyI:C innate immune challenge. Ten days of intragastric administration of ethanol in mice potentiates proinflammatory responses in brain to a lipopolysaccharide-TLR4 innate immune challenge which included CCL2, COX-2, gp91icroglia . Similaricroglia . These nicroglia . NeuroimTherapeutics under investigation for AUD often exhibit anti-inflammatory components. Given the critical role of the cholinergic system in regulating anti-inflammatory feedback, it is unsurprising that many of these restorative interventions center around the cholinergic systems. Rodent and human studies suggest successful therapeutic targets at both cholinergic muscarinic M4 receptors  and nicoThese mechanisms linking neuroinflammation and neurogenesis are particularly important when examining sex differences as human females are more likely than men to experience organ damage following long-term alcohol use, including greater brain damage in general and more specifically loss of hippocampal volume , and areThe molecular mechanisms of ethanol-related neuronal damage and related intervention strategies circulate around the cholinergic system, neuroinflammation, and the mechanistic mediators of these systems on hippocampal neurogenesis regardless of developmental window, suggestive of certain central commonalities within the effects of ethanol on these systems. However, across the neurodevelopmental landscape, while the mechanisms may overarchingly be consistent, various systems display differing sensitivities in the magnitude and reversibility of ethanol-related disruptions. For example, in models of FASD, ethanol produces seemingly irreversible deficits in the cholinergic system, and one of the key factors in treatment for FASD focuses on preventing rather than reversing this neuronal damage. If unmitigated, the irrecoverable loss of cholinergic neurons is a hindrance to the functional recovery of ethanol-related damage, and later life consequences of this disruption include greater neuroinflammatory responses and decreases in neurogenesis when neural systems are challenged. As females tend to be diagnosed with FASD later than males, this suggests that intervention strategies may be particularly difficult for this population as females have a greater likelihood of missing early intervention therapeutic windows.In contrast, adolescence is marked by epigenetic-mediated suppression of basal forebrain cholinergic phenotypes, which is exciting from a therapeutic standpoint as reversal of epigenetic machinery in cholinergic neurons similarly restores their phenotypic expression, which consequently also restores the hippocampal neuroinflammatory-trophic balance as well as ethanol-mediated deficits in hippocampal neurogenesis. This balance between persistence and reversibility after adolescent ethanol exposure highlights a shift in the mechanisms driving ethanol-induced loss of hippocampal neurogenesis and neurocognitive impairments from the cholinergic system as the central mediator to neuroimmune dysregulation playing a greater role.This shift becomes more apparent in adulthood, where hippocampal neuroimmune induction in both preclinical models and in human postmortem tissue from individuals diagnosed with AUD persists long after ethanol exposure and seem to drive long-term cellular consequences, including hippocampal damage and deficits in neurogenesis. While abstinence reverses some of these deficits in males, females exhibit greater sensitivity to ethanol-related brain damage, with emerging studies finding that females require more aggressive intervention strategies than males.in utero or in adolescence increases drinking behaviors at later developmental windows (The shifts in vulnerability of cholinergic versus neuroimmune systems over development suggests that efficacy of interventions aimed at restoring ethanol-related damage to hippocampal neurogenesis and cognitive function must take a developmental approach. However, a limitation of preclinical models of FASD, adolescent binge drinking, and AUD is that often alcohol exposure in humans is not isolated to a single developmental period. In fact, prior exposure to ethanol either  windows . Thus, a windows . This do


Objective: To examine differential relationships between communication technology use and social connectedness among paid and unpaid caregivers providing care for middle-aged and older adults. Methods: This nationwide study utilized a cross-sectional Qualtrics panel survey from caregivers, ages 50 years and older (n=504) of middle-aged and older adults. About 17% were paid (n=86) and 83% (n=418) were unpaid caregivers. Primary outcomes were caregivers’ sense of belonging to their local community and social bonds. The primary predictor of interest was caregivers’ use of communication technology (texting/communication applications). A multivariable regression analysis was performed to predict each outcome based on communication technology use, separately among paid and unpaid caregivers. Multivariable regression analyses were repeated after including the caregivers’ payment status (paid/unpaid) and the interaction term between the caregivers’ payment status and the use of communication technology. The models were adjusted for caregivers’ age, education, financial status, place of residence, and total weekly hours of caregiving. Results: Use of communication technology had a statistically-significant positive association with sense of belonging only among paid caregivers . The relationship between use of communication technology and sense of belonging was significantly different between paid and unpaid caregivers (p=.005). Use of communication technology was significantly associated with social bonds only among unpaid caregivers . There was no statistically-significant differential association between communication technology use and social bonds. Conclusion: Communication technology may play differential roles in linking paid and unpaid caregivers with their community and interpersonal groups. Additional efforts should examine mechanisms that provide meaningful caregiver support.


They report optimized diffusion at an intermediate temperature between cryogenic and room temperatures. Most commendably, they combined results from three distinct optical techniques to support their hypothesis for this non-monotonic temperature dependence. Photoluminescence measurements suggested phonon scattering was the predominant impediment to transport at higher temperatures, while Raman characterization of micro strains indicated that a 2D disorder potential was the primary obstacle at lower temperatures. Pump probe experiments and associated theoretical modeling were performed to further corroborate the hypothesis. While open questions remain on exciton transport in TMD monolayers, new and exciting opportunities are emerging for controlling exciton transport in van der Waals heterostructures.Excitons—charge-neutral quasiparticles comprised of bound electron hole pairs—can be formed within a wide range of semiconductors, including monolayer transition metal dichalcogenides (TMDs). The ongoing development towards practical excitonic devices necessitates a fundamental understanding of exciton transport in TMDs. Excitons in TMD monolayers exhibit ultrafast population relaxation times and correspondingly short diffusion lengths. In their article, Qi, Luo, and coworkers investigated how phonon scattering and disorder influence exciton diffusion in a WSe


Persistent postoperative pain (PPP) after cardiac surgery is a significant complication that negatively affects patient quality of life and increases health care system burden. However, there are no standards or guidelines to inform how to mitigate these effects. Therefore, in this review, we will discuss strategies to prevent and manage PPP after cardiac surgery. Adequate perioperative analgesia may prove instrumental in the prevention of PPP. Although opioids have historically been the primary analgesic approach to cardiac surgery, an opioid-sparing strategy may prove advantageous in reducing side effects, avoiding secondary hyperalgesia, and decreasing risk of PPP. Implementing a multimodal analgesic plan using alternative medications and regional anesthetic techniques may offer superior efficacy while reducing adverse effects. According to the International Association for the Study of Pain, PPP is defined as pain that persists beyond 3 months after surgery, can be continuous or intermittent, and is attributable to the surgical insult, excluding other potential etiologies. Up to 43% of patients suffer PPP at 3 months after cardiac surgery. A meta-analysis that included 11 057 cardiac surgical patients across 23 studies demonstrated a 37% incidence of PPP in the first 6 months and up to 17% at 2 years after surgery. A retrospective analysis of 35 817 cardiac surgical patients registered in a national administrative claims database of private payers revealed that nearly 1 in every 10 patients who were previously opioid naïve developed opioid use that persisted >3 months after surgery and associated higher oral morphine equivalents prescribed with an increased risk of persistent opioid use. Patients with PPP experience decreased health-related quality of life, effectively rendering the surgical intervention a means to displace the focus of their suffering instead of alleviating it. Beyond suffering, pain impedes critical postoperative rehabilitation, resulting in functional disability that prevents return to work and a normal life. On a larger scale, PPP can result in medicolegal actions, disparate economic impact, and increased medical costs and resource utilization.Persistent postoperative pain (PPP) is a devastating complication that affects both patients and health care systems. The incidence of moderate to severe PPP can vary widely based on surgery type, from <5% to >80% of cases performed. Risk factors for PPP after cardiac surgery include young age, female gender, preexisting pain, anxiety, a catastrophizing mindset, higher body mass index, and a history of osteoarthritis.7 Of note, more intense acute postoperative pain has been associated with a greater incidence and severity of PPP.7Of cardiac surgical patients with PPP, half have reported it to be moderate to severe and most have described it as neuropathic in quality, the primary location of pain in the chest, the next being the leg in patients having undergone saphenous vein harvesting.9 Likewise, aggressive preventive analgesia has been associated with decreased PPP. Therefore, adequate understanding and management of perioperative pain constitutes a fundamental strategy in PPP prevention following cardiac surgery. Risk factors for acute postsurgical pain include young age, longer duration of surgery, and thoracotomy, as compared with surgical access at other sites  receptor blocking activity of methadone, which has been associated with the prevention of opioid-induced hyperalgesia. A perioperative, opioid-sparing strategy utilizing analgesic alternatives and adjuncts may ultimately mitigate the risk of developing PPP and additional opioid-induced side effects, while also conferring additional benefits versus opioids alone.24 It is important to clarify, however, that prevailing evidence and expert opinion support opioid-sparing but not opioid-free techniques. Not only do opioids, when dosed in moderation, have longstanding efficacy, the absolute avoidance of them has actually been shown to cause harm.Cardiac anesthesia has historically relied on significant opioid administration due to their potent analgesia amid a favorable hemodynamic profile,tion see .15 Whe24 Acetaminophen, gabapentinoids, and ketamine have all been previously described as providing both effective analgesia and offering opioid-sparing benefit.28 Rafiq and colleagues conducted a prospective randomized controlled trial (RCT) examining multimodal analgesics versus opioids following cardiac surgery through median sternotomy. The authors found a combined regimen utilizing dexamethasone, gabapentin, ibuprofen, and acetaminophen provided superior analgesia (decreased numeric rating pain scores) through postoperative day 3 and decreased incidence of nausea and vomiting versus morphine and acetaminophen alone. Despite these findings during the acute pain period, a recent systematic review and meta-analysis regarding gabapentinoids observed no clinically significant analgesic effect to support their routine perioperative use. Further literature remains limited or not yet assessed regarding gabapentinoid use in the prevention of chronic poststernotomy pain.30The application of multimodal analgesics may play particular importance in preventing PPP as this more inclusive approach has been described as providing optimal acute pain management with potentially fewer side effects when compared with a traditional opioid-based strategy. With regard to acetaminophen (paracetamol) administration, the authors found 2 of 4 RCTs demonstrating significantly decreased Visual Analogue Scale (VAS) scores and one of these publications demonstrating significantly decreased opioid consumption.3134 Of 3 RCTs examining nonsteroidal anti-inflammatory drug (NSAID) analgesics and cardiac surgery, 2 trials demonstrated decreased VAS, and opioid consumption with NSAID use.36 Although the authors acknowledge the literature remains sparse regarding acetaminophen and NSAID use specific to cardiac surgery, Bignami and colleagues conclude that the use of multimodal analgesia provides synergistic pain relief with fewer adverse effects. Although VAS scores permit readily obtainable data gathering, more comprehensive assessments including functional and disability data may provide more reliable and objective measures in assessing pain. Direct comparisons of differing pain-related studies are often complicated by heterogeneity in outcome assessment and the use of non-patient-centric endpoints such as morphine equivalents. There are numerous validated patient satisfaction and quality of life questionnaires that better capture more meaningful outcomes related to improved pain control rather than relying on VAS scores alone.39A subsequent systematic review conducted by Bignami and colleagues examined perioperative pain management modalities and cardiac surgery including multimodal analgesics. Among the 40 RCTs with analgesics including NSAIDs, gabapentin, pregabalin, lidocaine, steroids, ketamine, NMDA blockers, fentanyl, nitrous oxide, venlafaxine, and the antiarrhythmic mexiletine, only intravenous ketamine provided a statistically significant, albeit modest, reduction in the incidence of postsurgical chronic pain. In a subsequent review of postoperative chronic pain prevention, Reddi similarly concluded that ketamine may reduce chronic pain after surgery while suggesting gabapentin and pregabalin as promising but requiring additional robust studies prior to recommendation. In a recent review of chronic poststernotomy pain, Kleiman and colleagues similarly found no evidence to support the use of transdermal lidocaine, glucocorticoids, or dexmedetomidine in decreasing chronic pain. In contrast, the authors acknowledge the effectiveness of acetaminophen, gabapentinoids, and ketamine in providing opioid-sparing analgesia, but describe their utility in preventing chronic poststernotomypain as limited or not yet examined.Beyond the acute postoperative period, the role of systemic pharmacologic therapies in preventing the development of chronic pain after surgery has also been examined. Chaparro and colleagues conducted a meta-analysis of RCTs with systemic drugs administered perioperatively and evaluated pain 3 or more months following surgery. Multimodal analgesics have often been combined with targeted regional anesthetic techniques to reduce opioid requirements, enhance pain control, and potentially reduce systemic analgesics and their accompanying side effects including delirium, hypotension, bradycardia, bleeding, and sedation. Neuraxial anesthesia serves as one regional technique that may be considered in cardiac surgery via thoracic epidural analgesia (TEA) or spinal anesthesia.44 TEA has been shown to provide effective analgesia with decreased VAS scoring and reduced opioid consumption postoperatively,27 yet no evidence supports a definitive decrease in developing chronic pain following TEA or intrathecal opioid administration. The risk of spinal hematoma has historically been shown to be 1:1528 for TEA and 1:3610 for spinal anesthesia, but the risk for TEA has more recently been shown to be as low as 1:3552. The 2018 guidelines released by the American Society of Regional Anesthesiologists states there is insufficient evidence to determine whether the risk of epidural hematoma with neuraxial procedures is increased with the use of the level of anticoagulation required for cardiopulmonary bypass (CPB). The decision to employ neuraxial anesthesia as part of any opioid-reducing analgesic strategy should always consider a risk-benefit calculation regarding epidural hematoma formation in the vulnerable cardiac surgery patient population.49The application of regional anesthesia provides a diverse array of potentially opioid-sparing pain management methods in accordance with a multimodal analgesic strategy. The ability to administer local anesthetics through regional anesthesia may be particularly favorable in high-risk surgical candidates as these techniques may reduce or outright avoid adverse effects associated with opioid administration.4952 The risk of epidural hematoma formation proves notably relevant within cardiac surgery due to the frequent anticoagulation requirement for patients undergoing cardiopulmonary bypass. Similar to TEA, there exists no evidence to support thoracic PVB in the prevention of chronic poststernotomy pain.Thoracic paravertebral block (PVB) serves as alternative regional anesthetic technique utilized for analgesia related to cardiac surgery. Thoracic PVB consists of a type of peripheral nerve block with option for continuous catheter placement similar to TEA, yet PVB may be performed under direct ultrasound guidance. When compared with TEA, thoracic level PVB has been found to provide comparable analgesic efficacy and improved side effect profile, including theoretically less risk of epidural hematoma formation in the anticoagulated patient.27 without effect on chronic pain development. Similarly, ultrasound-guided parasternal intercostal nerve block performed presternotomy has demonstrated significantly lower postoperative pain scores versus saline injection or nonregional, morphine-based regimen. Studies assessing intrapleural block for sternotomy pain are limited, and similar to continuous wound catheters, have not yet examined their relationship with regard to developing PPP.Various other regional anesthetic techniques including emerging, ultrasound-guided peripheral nerve blocks have been applied for poststernotomy analgesia and cardiac surgery at large. Surgeon administered parasternal block has been shown to provide improved postoperative analgesia and reduced opioid requirements,55 The erector spinae plane (ESP) block presents a novel fascial plane block that was first described in 2016 for thoracic neuropathic pain and has since been applied as an easier to perform alternative to PVB to multiple procedure types involving the chest wall and abdomen.57 Few clinical studies assessing the ESP block for cardiac surgery have taken place, but initial data reveal promising analgesic efficacy and reduction in opioid consumption, while the need for replication via blinded RCTs persists.58 Similar analgesic studies have evaluated both the pectoral nerve and serratus anterior fascial plane blocks with encouraging results. The pectoralis (Pecs) nerve block entails dual interfascial plane injections (Pecs I and Pecs II) with the aim of anesthetizing the chest wall. Kumar and colleagues examined postoperative bilateral pectoralis nerve block following midline sternotomy, demonstrating both significantly decreased duration of ventilator dependence and improved pain scores utilizing the regional technique. Currently, no published evidence exists evaluating the more laterally performed serratus anterior nerve block approach specific to sternotomy pain, yet studies have shown improved pain scores following other thoracic surgical interventions.Promising, emerging peripheral nerve blocks of the chest wall occur most often using direct visualization with ultrasound guidance, potentially adding to their safe application.62 Through incorporation of multiple individuals, a multidisciplinary, perioperative pain team may optimally treat complex pain through specialization, communication, and education among providers and patients. Such a team would be well positioned to combine clinical management with pain research.In addition to the consulting anesthesiologist’s role in managing opioid-sparing, multimodal analgesia, a multidisciplinary approach may provide the ideal strategy in preventing PPP in the cardiac surgery patient.63 Because mediastinitis has been associated with developing chronic pain, the more selective skeletonization harvest may prove warranted, particularly in the diabetic patient population. Minimizing sternal retractor trauma, removing sternal wires posthealing, and prophylactic sternal plating in high-risk individuals has been suggested to minimize chronic pain contributions. Minimally invasive techniques have been used to decrease the degree of tissue traumatization, acute postoperative pain, intraoperative time, perioperative bleeding, and the incidence of sternal wound infections and recovery time. In addition, the removal of chest drainage tubes on the first postoperative day, as compared with days 2 or 3, has been associated with improved pain scores without an increased risk of requiring chest tube reinsertion.Procedural considerations should be discussed with surgical colleagues as multiple operative variables may influence the development of PPP. For example, obtaining bilateral internal thoracic artery grafts via pedicled harvest rather than skeletonization has been associated with an increased risk of developing mediastinitis after coronary artery bypass graft (CABG). exacerbates acute postoperative pain. Despite the likelihood of a link between this altered pathophysiologic state and sensitization to pain signaling, this mechanism has not been investigated. There have been numerous studies comparing patients having undergone CABG surgery performed either with or without CPB, but none have specifically evaluated differences in pain following these techniques.Surprisingly, it is unknown if the well-described state of heightened systemic inflammation associated with the use of CPB68 Interestingly, patients on cannabinoids may have higher tolerance to opioids and NSAIDs, requiring higher doses.There are some classes of home medications that may affect perioperative analgesia. To optimize analgesia while minimizing relapse and overdose, it is recommended for patients taking low-dose buprenorphine and methadone to continue those medications throughout the perioperative period.7074 Early involvement of a pain psychologist or integrative pain team may offer valuable insights to both identify and address these psychological risk factors outside of the cardiothoracic anesthesiologist and surgeon’s area of expertise.75Addressing patients’ psychological comorbidities may also play a key role within a multifaceted approach to PPP prevention after cardiac surgery. Patients may present with preexisting psychological risk factors for the development of chronic pain including anxiety, depression, posttraumatic stress disorder, and pain catastrophizing.7679 Multimodal analgesia has remained central to ERAS protocols as this strategy may offer decreased opioid exposure in addition to potentially reducing recovery times, complications, and improving cost expenditures with surgery.81 Similarly, regional anesthesia has been increasingly implemented as part of a multimodal strategy in cardiac surgery and related ERAS protocols to reduce opioid consumption.83 The addition of emerging truncal fascial plane blocks for pain optimization presents a promising new area within cardiac ERAS.84 Because cardiac ERAS pathways often highlight opioid-sparing strategies and acute pain management optimization,86 implementation of these protocols aligns with addressing the aforementioned factors thought to contribute to PPP.Many of the aforementioned pain management components and multidisciplinary approach relevant to cardiac-related PPP have been integrated as part of comprehensive, enhanced recovery after surgery (ERAS) protocols. ERAS pathways including those specific to cardiac surgery continue to gain popularity and aim to incorporate multiple objective variables to optimize patient experience, perioperative efficiency, and improve outcomes.Although prevention is likely the most impactful strategy to decrease the burden of PPP after cardiac surgery, this may not always be possible. There are a variety of treatment options for PPP including medications see , surgery88 Indeed, the most updated 2015 Food and Drug Administration (FDA) black box warning for non-ASA NSAIDs advises against their use in patients prior to or after CABG, emphasizing the potentially increased risk for heart attack or stroke in patients with underlying cardiovascular disease. Furthermore, the use of non-ASA NSAIDs for cardiac surgical patients has been associated with acute kidney injury, whereas ASA use has been shown to be protective.Medical management of PPP involves targeting the various pathways and mechanisms of pain. NSAIDs decrease the production of inflammatory cytokines and chemokines such as prostaglandins. This may be particularly helpful in the acute phase of injury for patients, but also plays a role in chronic musculoskeletal pain and associated flares. Both the acute and long-term risks of NSAID use needs to be considered, especially in the cardiac surgery population, and the distinction between acetylsalicylic acid (ASA) and other NSAIDs is warranted. Renal injury, increased risk of myocardial infarction and stroke are all potential adverse events that the cardiac surgery population may already have a higher baseline risk for developing when using non-ASA NSAIDs. There is evidence that it inhibits COX centrally and acts through other non-COX mechanisms as well. This agent has a better safety profile without a demonstrated association with hepatic dysfunction, although caution should be taken in patients with acute liver injury.Acetaminophen or paracetamol is a known cyclooxygenase (COX) inhibitor, although it does not exert its effect through peripheral inhibition of this enzyme as the non-steroid anti-inflammatory class of medications.5 These agents have a generally favorable safety profile with nausea, sedation, and dizziness being some of the more common side effects and caution should be taken for patients with baseline renal dysfunction.Gabapentin and pregabalin bind to the alpha2delta subunit of calcium channels and are used in treating many different types of chronic pain. They are most well studied and effective for neuropathic pain. For cardiac surgery patients that have a neuropathic component to their pain, these may be a reasonable treatment option and studies have shown that approximately half of cardiac surgical patients with PPP do have a neuropathic component to their pain. The primary site of action is likely augmentation of the descending inhibitory pathways, although there are likely additional mechanisms of action that provide analgesic benefit. SNRIs including duloxetine have been studied for a variety of neuropathic pain conditions and shown to provide significant benefit. For most patients, SNRIs are better tolerated and have a better side-effect profile when compared with TCAs.Additional neuropathic agents including serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) may also play a role in the management of PPP that has a significant neuropathic component.There is limited evidence regarding the use of dexamethasone specifically regarding the treatment postoperative pain in cardiac surgery patients. One randomized double blinded, placebo-controlled study of 300 postoperative patients who had coronary revascularization surgery did not find a difference in opioid consumption or severity of postoperative pain for the first 2 days after surgery. Patients should have treatment goals that may include pain reduction and functional improvement and they should respond favorably to low doses of opioids. Practically, the number of patients who should require and would benefit from chronic opioid therapy is likely low, although this has not been studied in this population.Chronic application of opioids needs to be carefully weighed with the risks. Chronic use needs to be carefully monitored and the appropriateness of ongoing therapy evaluated by pain management specialists.99 Cryoablation of neural tissue has been utilized for treatment of various painful conditions. The first study of cryoablation of the intercostal nerves was done in 1980 for pain associated with thoracotomy and reported significantly reduced analgesic use in the group that received the intercostal cryoablation. Perhaps the most relevant study pertinent to this review was done in 2000 for patients undergoing minimally invasive cardiac surgery via minithoracotomy. This study reported reduced pain scores, although no difference was seen in analgesic consumption. Neuromodulation is a field that has continued to develop and there are case reports and small studies of patients who may benefit for spinal cord stimulation for chronic, refractory angina or in one case truncal complex regional pain syndrome following sternotomy.103 A limitation of these techniques may be anticoagulation for patients with cardiovascular disease and further research is needed to determine which patients would benefit most from these advanced and more invasive techniques. Surgery can also be an option for a small subset of patients who have a clear mechanical component to their pain. This would include patients with sternal malunion or sternal wire fracture, although these are relatively rare complications and are likely not significant contributors to PPP for most patients.Beyond medical management, interventional pain procedures may be appropriate for certain patients. Patients who have had a minimally invasive procedure performed via thoracotomy may develop intercostal neuralgia or post-thoracotomy pain. Treatment with intercostal nerve blocks, paravertebral blocks, trigger point injections, or thoracic epidural steroid injections may be treatment options. Treatment of chronic pain is an off-label use for most of these therapies given the relatively limited evidence, but for patients with refractory pain they may be appropriate to trial. Depending on the characteristics and location of the patient’s pain, topical agents such as lidocaine, diclofenac, or capsaicin can be considered. In patients with muscle spasms or myofascial pain, muscle relaxants  can provide some symptom relief. Physical therapy is important for recovery in strength and function after surgery, but there can be further benefits for patients who go on to develop chronic pain. Dry needling can target pain with a myofascial component and therapists can work to improve function in patients who are deconditioned due to inactivity from their pain. Psychological therapy in the form of cognitive behavioral therapy, cognitive function therapy, acceptance and commitment therapy, biofeedback, and mindfulness can be helpful for patients with chronic pain, particularly when there are complicating psychosocial factors. The importance of a comprehensive approach to the treatment of chronic pain with therapy , medication, interventions, and adjunctive therapies cannot be understated.For refractory neuropathic pain antiepileptic agents , NMDA receptor antagonists such as memantine and infusions including ketamine or lidocaine are treatment options to consider.PPP and opioid use remain vital pain management concerns in providing optimal anesthetic care surrounding cardiac surgery. Further best practices data are required through future research study in multiple areas including the following:Further studies identifying patient risk factors for the development of PPP after cardiac surgeryResearch needed to assess the effect of cardiac surgical procedure type and intraoperative interventions on pain outcomesResearch examining the inflammatory state and role of intraoperative CPB use in the development of chronic painResearch addressing the consequence of acute pain management and its effect on the development of PPPLarge-scale RCTs assessing systemic, multimodal analgesics in the development of chronic pain following cardiac surgeryLarge-scale RCTs evaluating regional anesthesia applied to cardiac surgery and the development of chronic painHead-to-head comparative studies assessing novel, ultrasound-guided regional anesthetic techniques with cardiac surgeryResearch assessing secondary hyperalgesia therapies as potential preventative measures to developing chronic painResearch needed to assess the effect of psychological and behavioral interventions on the development of chronic postsurgical painLarge-scale RCTs assessing ERAS pathway implementation and the development of chronic painLarge-scale RCTs evaluating neuromodulation and spinal cord stimulator therapy for chronic poststernotomy pain106 Current literature suggests both prevention and treatment of PPP should optimally include multimodal pharmacology, regional anesthesia, and multidisciplinary involvement.62 Future research is required in this vulnerable patient population to confirm best practices in PPP prevention and treatment as part of an enhanced recovery after cardiac surgery pathway.Persistent postoperative pain after cardiac surgery represents a significant complication negatively affecting patients and health care systems. Adequately treating acute pain following cardiac surgery remains paramount as severe postoperative pain and opioid-induced hyperalgesia may increase the risk of developing PPP.


OBJECTIVES/GOALS: Environmental factors may significantly increase the risk of or buffer against Alzheimer’s disease and related dementias, yet strategies to address cognitive decline and impairment to date largely overlook the role of neighborhoods. This mixed-methods study is the first to examine potential links between access to eateries and cognitive function. The goal is to inform place-specific interventions to help aging individuals reduce risk for cognitive impairment through neighborhood community and design. METHODS/STUDY POPULATION: Following an exploratory sequential mixed-methods design, seated and mobile interviews with 125 adults aged 55-92 (mean age 71) living in the Minneapolis (Minnesota) metropolitan area suggest that eateries, including coffee shops and fast-food restaurants, represent popular neighborhood destinations for older adults and sources of wellbeing. To test the hypothesis that these sites, and the benefits they confer, are associated with cognitive welfare, we analyzed data from urban and suburban dwelling participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a national racially diverse sample of older Americans followed since 2003 . RESULTS/ANTICIPATED RESULTS: Qualitative thematic analysis of how older adults perceived and utilized local eateries include sites of familiarity and comfort; physical and economic accessibility; sociability with friends, family, staff, and customers; and entertainment . Quantitative results from multilevel linear regression models demonstrate a positive association between density of eateries and cognitive functioning. Taken together, these results complicate our understanding of fast-food settings as possible sites of wellbeing through social interaction and leisure activities. DISCUSSION/SIGNIFICANCE OF IMPACT: The results contribute new evidence towards an emerging ecological model of cognitive health. Understanding whether and how retail food environments can help buffer against cognitive decline among older adults provides novel opportunities to promote wellbeing in later life through community interventions and neighborhood design.


Long implicated in aversive processing, the amygdala is now recognized as a key component of the brain systems that process rewards. Beyond reward valuation, recent findings from single-neuron recordings in monkeys indicate that primate amygdala neurons also play an important role in decision-making. The reward value signals encoded by amygdala neurons constitute suitable inputs to economic decision processes by being sensitive to reward contingency, relative reward quantity and temporal reward structure. During reward-based decisions, individual amygdala neurons encode both the value inputs and corresponding choice outputs of economic decision processes. The presence of such value-to-choice transitions in single amygdala neurons, together with other well-defined signatures of decision computation, indicate that a decision mechanism may be implemented locally within the primate amygdala. During social observation, specific amygdala neurons spontaneously encode these decision signatures to predict the choices of social partners, suggesting neural simulation of the partner’s decision-making. The activity of these ‘simulation neurons’ could arise naturally from convergence between value neurons and social, self-other discriminating neurons. These findings identify single-neuron building blocks and computational architectures for decision-making and social behavior in the primate amygdala. An emerging understanding of the decision function of primate amygdala neurons can help identify potential vulnerabilities for amygdala dysfunction in human conditions afflicting social cognition and mental health. Here weThe amygdala is a collection of nuclei located in the anterior part of the medial temporal lobe. It participates in a range of functions including emotion, learning, memory, attention and reward-guided behavior. Based on its anatomical connections, classical views considered the primate amygdala an interface between (i) hypothalamic and brainstem areas related to endocrine and autonomic functions, and (ii) limbic and neocortical regions related to cognitive functions . The amyEarly lesion studies suggested that amygdala damage in monkeys affects an animal’s ability to identify reinforcing stimuli . SubsequIn the present review, we focus on the neuronal signals mediating the primate amygdala’s more recently acknowledged functions in economic decision-making and in predicting others’ decisions in social contexts. We also consider key factors that influence the reward signals of amygdala neurons, which provide important inputs to decision processes.2Primate amygdala neurons respond to conditioned, reward predicting stimuli and track the changing value of these stimuli during learning . AccordiThese theoretical concepts demand to ask whether conditioned reward processing in amygdala neurons follows reward contingency rather than reward pairing. Lesions in the amygdala make rats insensitive to changes in background reward, indicating a general role in contingency-dependent learning . To follThus, typical reward-conditioned responses in primate amygdala neurons reflect reward contingency rather than stimulus-reward pairing. Such acquired responses to reward-predicting stimuli would constitute useful inputs to neuronal mechanisms underlying informed economic decision-making. The specific mechanisms by which amygdala neurons process reward contingency from comparing stimulus-based reward and background reward remain to be uncovered.3Given that amygdala neurons acquire responses to rewarding events  and thatReward amount scaling is reflected in the responses of primate amygdala neurons to reward receipt : these rThe amygdala neurons reviewed above faithfully identify by their response which reward is the better one in any changing distribution of rewards. This quantitative reward code could provide critical inputs to an economic decision process. An important open question is whether the same amygdala neurons that encode quantitative reward-magnitude information are also sensitive to reward probability. Processing of both reward probability and magnitude in individual amygdala neurons would provide a substrate for computing key statistical properties of reward distributions, including expected value and variance.4The predicted time of future reward fundamentally affects behavior, as evidenced in the temporal difference model of reinforcement learning  and the The forms of sensitivity to temporal reward structure described above would allow amygdala neurons to participate in timing processes underlying learning and decision-making. Recent studies, described below, uncovered time-sensitive amygdala signals in decision tasks that require planning ahead and tracking progress over extended periods ,5. Howev5Neuronal decision processes involve the translation of graded, parametric value signals, reflecting the evidence for the decision, to signals predicting the animal’s categorical choice. Primate amygdala neurons seem well suited to contribute to such reward-based decision processes. As described above, their flexible, context-sensitive value signals provide a substrate for integrating relevant evidence to decision inputs. An explicit choice signal computed from such values could also be broadly distributed by the amygdala, given its diverse efferent connections. Furthermore, lesions studies demonstrated essential amygdala contributions to decision-related processes including reinforcer devaluation ,44, stimIn a series of studies, we examined the activity of primate amygdala neurons in a sequential economic decision-making task ,4,5. In During performance of the save-spend task, a significant number of amygdala neurons predict the monkeys’ save-spend choice on individual trials . These cMore recent findings extend our beginning understanding of the amygdala’s decision functions. One study examined amygdala neurons in monkeys tracking the changing values of multiple visual stimuli and balancing exploration-exploitation decisions . During The data reviewed above suggest that primate amygdala neurons play a much more direct role in decision-making than traditionally thought. Specifically, the observation of explicit value-to-choice transitions in individual neurons  and othe6The best rewards are often distant, requiring careful planning and stepwise, sequential choices to reach internally set goals. In the save-spend task described above , amygdalA distinct type of amygdala neuronal activity observed in the save-spend task explicitly signals the monkeys’ progress through a saving sequence . ProgresThus, the activity of amygdala neurons reflects the value and temporal structure of an animal's plan to obtain distant reward goals, and tracks the stepwise progress toward that goal. By specifying prospective reward goals, these amygdala signals could provide direction for behavioral plans encoded in frontal lobe areas ,55. This7Primates do not only make choices individually but also observe the choices of their social partners. By observing their partners, primates can learn the values of objects to inform own decision-making and to predict their partners’ choices and intentions. The amygdala may play an important role in these social processes. Its neurons process social cues, such as faces  and amygA recent study examined the activity of amygdala neurons in a social situation in which two monkeys observe and learn from each other’s reward-based choices B. BeyondThe observed functional types of amygdala neurons C suggestThe amygdala is unlikely to perform these sophisticated operations in isolation. The anterior cingulate cortex contains neurons that predict partner’s choices during competitive interactions , neuronsThus, recent data suggest important contributions of primate amygdala neurons in social decision-making and predicting others’ choices. These data may help explain the effects of amygdala lesions on social behaviour ,61, the 8The findings reviewed above suggest an emerging account of how amygdala neurons and circuits contribute to individual decision-making and social decision simulation. A role for the primate amygdala in implementing a decision mechanism is consistent with observed value-to-choice conversions in individual amygdala neurons , with adHow do amygdala decision signals relate to decision signals found in other brain structures? The amygdala and orbitofrontal cortex receive prominent sensory inputs from all modalities , which pThe reviewed parallel neurophysiological studies on amygdala decision and social functions also inform the broader question of whether the amygdala is specialized for social behavior, as suggested by the Social Brain Hypothesis , or whetThe decision signals and planning activities in amygdala neurons described above may inform our understanding of amygdala dysfunction in human psychiatric conditions, including mood disorders that impact on the motivation to make decisions and pursue future rewards . The amyNone.


While the development of communication competencies in medical schools plays a pivotal role in the curriculum, studies show that students’ communication skills and patient-centred attitudes may vary based on gender and ethnicity. The goal of this study was to investigate the socio-demographic factors that influence medical students’ communication abilities and, more specifically, to what extent their attitude toward communication skills learning and patient orientation associate with communication abilities. Our population included medical students admitted in 2017. Used tools included a communication score, the patient-provider orientation and communication skills attitudes scales.. There was a significant association between gender, native tongue, attitudes towards communication skills learning and communication skills OSCE performance. In conclusion, to support medical students to improve their communication proficiency and attitudes towards the importance of clear communication and patient-oriented care, medical educators should consider teaching and assessment strategies that address socio-cultural aspects of communication.Three hundred and sixty-five students participated in the study . Female and German native speaking students had a better communication skills OSCE performance, were more patient-oriented and had more positive attitudes toward communication skills learning than male and non-native speaking students One of the main roles of a physician articulated in national medical curriculum frameworks of learning objectives is being a communicator . DespiteThe main method to assess medical students’ communication skills are the objective structured clinical examinations (OSCEs). Widely used as an outcome measure for academic success in medicine, OSCEs generally assess students’ knowledge and skills in history taking, diagnostic tests interpretation, communication, and physical examinations and were shown to improve students’ communication skills . Given tPhysicians’ competencies are referred to in curriculum documents as medical knowledge, clinical skills and professional attitudes . AlthougMedical students’ declining positive attitudes toward social issues  raise coThe goal of this study was to address this gap and investigate which factors influence medical students’ communication skills OSCE performance and, more specifically, to what extent medical students’ attitudes towards communication skills learning and patient orientation are associated with the communication skills OSCE performance.This is an observational study examining communication competencies of medical students at one German medical school. Students had started studying medicine in 2017 and were in their second or third year of study. At the end of the fourth and fifth semester, students take two in person OSCEs containing ten five minutes stations  , 13 and Socio-demographic data as well as data on attitudes towards communication skills learning and patient orientation were collected as part of a survey conducted electronically at the end of the OSCE.Patient orientation was measured with the patient-provider orientation scale . The insAttitudes towards communication skills learning were assessed with the communication skills attitudes scale (CSAS) . The CSAThe data were collected between July 2019 and February 2020.We report on descriptive analyses of socio-demographic characteristics and communication skills OSCE performance. A one-way between subjects ANOVA/post hoc Bonferroni procedure was conducted to compare the effect of mother tongue on the communication score. We used the T-test to investigate the effect of gender on the communication skills OSCE performance, attitudes towards communication skills learning and patient orientation. Correlation coefficients and backward multiple linear regression models were then calculated to investigate the extent to which gender, mother tongue, attitudes towards communication skills learning and patient orientation are associated with the communication skills score.The sample consisted of 365, 2nd or 3rd year medical students who completed all five stations of the composite communication skills OSCE. Students were aged on average 24.8 (± 3.5) years; the majority were female  and German native speakers .There was a significant effect of mother tongue on students’ communication skills OSCE performance, attitudes towards communication skills learning and patient orientation. The communication skills score of native speakers and bilingual medical students was significantly higher than the communication skills score of non-native speakers. German native speakers reported significantly lower NAS and more positive patient oriented attitudes than bilingual or non-native speakers. Female students scored higher on PAS and the communication skills score, lower on NAS and were more patient oriented than male students. Age seemed to play a role in attitudes development in that older students reported more positive and less negative attitudes towards communication skills learning Table .Table 2DOur regression model explaining 20.7% of the variance revealed that expressing less negative attitudes towards communication skills learning, being a native speaker, and female gender were significantly associated with a higher communication skills score. Positive attitudes, age and patient orientation were excluded from the model due to lack of statistical significance Table .Table 3RA composite OSCE focused on communication skills was developed to investigate associations between medical students’ communication skills OSCE performance, attitudes towards communication skills learning, patient orientation and socio-demographic characteristics.In our study, we found gender differences in the communication skills score in favour of women, a finding which is in line with previous research , 16, 17.Native speakers as well as bilingual students had significantly better communication skills scores than non-native speaking students. This gap in exam results was also observed in studies from the Netherlands and the UK, which showed that students that belonged to specific ethnic minority groups underperformed in communication and clinical problem-solving tests , 18. LanThe communication skills score in our study was associated with less NAS, a finding which is congruent with previous research that indicated a link between poorer communication skills and less patient-centred attitudes . BesidesIn conclusion, medical educators need to consider different curriculum design approaches to address attitudes and socio-cultural aspects of communication skills. Such approaches include: supporting peer assisted learning and assessment methods  to encouThis study was conducted at one university in Germany. However, research results are coherent with previous international findings and therefore relevant to an international audience of medical educators. This is a cross-sectional study on students’ communication skills in the first half of their studies. A longitudinal study design that allows the observation of attitudes and skills evolution could strengthen claims of decline in communication skills as students progress towards graduation. Finally, we used a validated tool for the self-reporting of attitudes towards communication skills learning. A direct observation of attitudes may have yielded a more robust assessment. Future research should address these gaps as well as the effectiveness of curriculum interventions as proposed above by using both quantitative and qualitative research methods.


As examples, the present commentary tries to integrate responses of AHR and NAD+-consuming enzymes  into infectious and stress-induced inflammatory responses, the latter exemplified by nonalcoholic fatty liver disease (NAFLD). TCDD toxicity models in sensitive species provide hints to molecular AHR targets of energy metabolism including gluconeogenesis and glycolysis. AHR research remains challenging and promising.Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert cellular stress-mediated sterile inflammatory responses in exposed human tissues but may be lethal in sensitive species. Inflammation can be thought of as the extreme end of a spectrum ranging from homeostasis to stress responses (sterile inflammation) and to defense against infection (infectious inflammation). Defense against bacterial infection by generation of reactive oxygen species has to be strictly controlled and may use up a considerable amount of energy. NAD Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. AHR has been characterized as ligand-activated, multifunctional transcription factor and environmental sensor  is known to exert sterile inflammatory responses in exposed tissues  the commentary tries to integrate functions of AHR and NAD+-consuming enzymes in infectious and sterile inflammatory responses. TCDD toxicity models in sensitive species are discussed since they provide hints to molecular AHR targets in energy metabolism.Elucidation of AHR functions is challenged by dependence upon cell type, cellular context, and species differences, the latter suggested by TCDD toxicity in sensitive species leading to wasting syndrome and lethality  or a chain of ADPR units to proteins. PARP1 is the most abundant and best studied enzyme and belongs to the poly(ADP-ribosylating) proteins. It is mostly involved in DNA repair. With regard to cooperation with AHR, TCDD-induced PARP7/TiPARP (TCDD-inducible PARP) has been characterized as repressor of AHR expression   may stimulate anti-inflammatory responses and prevent NASH  and sterile inflammation  as examples.Accumulating evidence suggests that AHR is involved in infectious and sterile inflammatory responses. These processes may use up a considerable amount of energy. Therefore, energy metabolism has to be metabolically adapted  have been demonstrated. In addition, both AHR and CD38 are constituents of a signalsome of neutrophils (Bunaciu et al. Multiple sources of endogenous, phytochemical and microbial AHR ligands have been identified allowing intense interaction of the receptor and sensor between barrier organs and the environment. Connections between AHR and NAD+-consuming enzymes in tissue-dependent inflammatory diseases have been discussed using two examples: infectious colitis and obesity-mediated NAFLD and NASH. In intestinal inflammation, beneficial effects have been discussed in homeostasis, microbial defense and the resolution phase of inflammation, provided that AHR is transiently activated. In NASH, both AHR and CD38 may be involved in anti-inflammatory processes. Therefore, both AHR-activating and CD38-inhibiting phytochemicals and microbial products as well as NAD+ boosting compounds may provide therapeutic options. However, anti-inflammatory tolerance mechanisms bear the risk to facilitate autoimmune diseases and carcinogenesis. Therefore, clinical studies have to evaluate risks and benefits in particular cases. The discussed perceptions may be applicable to inflammatory diseases of other organs including skin and lung.Roles of AHR and NAD+-dependent nuclear SIRT1 and mitochondrial SIRT3 as key regulators of gluconeogenesis and glycolytic enzymes. Hence, AHR research remains a challenging and promising field.TCDD toxicity is known to be species dependent leading to wasting syndrome and lethality in sensitive species (Poland and Knutson


Cancer is one of the primary causes of death that can affect any organ of the body. Cancer originates from transforming normal cells to tumour cells that often rapidly propagate and invade into adjoining tissues. Cancer cells spreading into other tissues are so called metastases, which is highly associated with death in humans. As to the World Health Organization, lung, colon and liver cancers are among the top ranked cancer types with high mortalities in recent years. The burden of cancer can be largely reduced with proper prevention, early diagnosis, effective treatment, and appropriate palliative care. Cancer treatment remains challenging, largely due to the complexity of its etiology and frequent occurrence of drug resistance.Targeted therapies are preferably adopted in cancer treatment for years. Such treatment alone or in combination with conventional chemotherapies have improved the survival of many cancer patients including those with tumours considered as incurable. Although clinical successes have been achieved in many cases, the failure rate of cancer targeted therapies remains disappointingly high. This is possibly due to the misapplication of therapies targeting pan-essential genes, the dysfunction of which leads to dose-limiting toxicities and/or the compromised therapeutic efficacy resulted from drug resistance.Drug resistance is either early intrinsic or late acquired . The verDrug resistance is the primary obstacle to achieve satisfactory clinical outcomes in carcer targeted therapies as numerous patients are inherently or adaptively resistant to existing regimens. Furthermore, there are deadly cancers without effective systemic therapies at present, like human uveal melanoma  and gastProteins that play essential roles in cell division, cell cycle progression and/or cell death continue to be valid therapeutic targets in cancer treatment. For instance, histone deacetylases (HDACs) that are enzymes responsible for removing acetyl groups from proteins, are widely involved in cellular processes. Their inhibitors have shown clinical potentials against specific malignancies and are under pre-clinical and clinical evaluations to treat various cancers .As to gastroesophageal cancer , targeted therapies against EGFR/HER signalling have been extensively evaluated. Despite the reduced side effects compared to that of conventional chemotherapies, a panel of tyrosine kinase inhibitors (TKIs) downregulating EGFR/HER signalling yielded unsatisfactory outcomes in clinical trials. Thus, emerging drug targets like the store-operated Ca2+ entry (SOCE) , attractDrug resistance pronouncedly compromises the clinical effectiveness of cancer therapies; there are multiple mechanisms contribute to such therapeutic defect. ATP binding cassette (ABC) transporters are important membrane proteins responsible for cellular efflux of substances including many commonly used drugs. Overexpression of ABCs has been widely observed in tumour cells, which notably leads to clinical failure of cancer targeted therapies . One of In colorectal cancer, irinotecan is clinically used in treating its metastatic disease. It is known that ABCG2/BCRP-mediated drug resistance remarkedly impacts on the pharmacokinetic performance of irinotecan and consequently, limits the clinical applications of this agent . The inein silico analysis have both been adopted to design adjuvant cancer regimens. Overexpressed oncogenes and common biological processes like ubiquitination are preferable targets for adjuvant therapies. Computer modelling-facilitated chemical modification has been widely applied in designing combined therapies in addition to traditional chemotherapies such as cisplatin and doxorubicin with severe side effects. The pre-clinical tests regarding these adjuvant regiments are often conducted on malignant cell lines and tumour xenograft models. However, clinical predictions based on these studies may be suboptimal due to the loss of tumour characteristics in immortalised cell lines and expected species differences between human and animals. Therefore, it is highly desired that confirmative evaluation can be performed on tumour tissue-derived primary cell lines, which better preserve tumour characteristics and genetic variations.Empirical approaches and One emerging area in cancer drug research is the incorporation of machine learning algorithms with the advance of artificial intelligence . With thIt is thought that novel drug delivery carriers can greatly improve effectiveness, safety and targetability of agents. Research has widely investigated unconjugated or conjugated liposomes, polymeric micelles, microspheres and nanoparticles in delivering cancer targeted therapies. The advance in drug delivery technology adds credits to existing cancer targeted therapies with enhanced stability and biocompatibility, improved targeting as well as reduced drug resistance . The draOverall, the ongoing battle against drug resistance associated with cancer targeted therapies is a great challenge in biomedical research. Continuous efforts, multidisciplinary collaborations and long-term monitoring will be required to ensure the progress in this field.


ABSTRACT IMPACT: Understanding how perceived discrimination affects Asian Americans can help stakeholders target subgroups that are at highest risk of discrimination-related behaviors and design culturally appropriate interventions to ensure equitable access to healthcare. OBJECTIVES/GOALS: The COVID-19 pandemic has exposed longstanding anti-Asian racism in the US. Yet, effects of discrimination on Asian American health are unknown, partly because diverse Asian American populations are analyzed in aggregate. We aim to understand how perceived discrimination affects healthcare utilization among different Asian American subgroups. METHODS/STUDY POPULATION: We examine the association of perceived discrimination with healthcare utilization using the California Health Interview Survey (CHIS). In the CHIS, respondents reported whether they would’ve gotten better medical care if they belonged to a different race. We examine the association between these responses and physician visits within the past year, in the survey years 2003, 2004 and 2016-2017. We adjust for covariates based on the Andersen Health Behavior model. Subsequent modeling examines potential mediating and moderating factors such as limited English proficiency, immigration status, income, and survey year. Asian American subgroups analyzed include Asian Indian, Korean, Chinese, Filipino, Vietnamese, Japanese, and other Asian. RESULTS/ANTICIPATED RESULTS: Results will highlight how perceived discrimination incentivizes or disincentivizes certain Asian subgroups to utilize healthcare. Asian American subgroups have differing and diverse experiences with discrimination due to their historical and cultural differences; results will elucidate how discrimination affects these subgroups. Results will be compared to non-Hispanic Whites, who represent the racial group least likely to experience discrimination in the US. Mediation and moderation analysis will help understand how traditionally cited factors for healthcare utilization interact with perceived discrimination on Asian Americans. DISCUSSION/SIGNIFICANCE OF FINDINGS: Asian American subgroups are understudied, despite Asian Americans being one of the fastest growing racial groups in the US. Understanding how perceived discrimination affects Asian Americans can help stakeholders target subgroups that are at highest risk of discrimination-related behaviors and design culturally appropriate interventions.