Peripheral inflammatory biomarkers define biotypes of bipolar depression.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/ß) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

Investigating Gender Differences in Canadian Plastic Surgery Online Patient Education.

BACKGROUND: The public interest and demand for cosmetic surgery is growing in North America. As practices continue to advertise cosmetic procedures, male consumers must also be given fair consideration in a market targeted mostly towards women. OBJECTIVES: This study investigated the advertising trends of plastic surgery clinics to assess for prevailing gender differences among online Canadian plastic surgery practice advertising. METHODS: The 2021 College of Physicians and Surgeons directory for each province and territory was utilized to identify all practicing plastic surgeons. A systematic search with Google (Mountain View, CA) was conducted to analyze the websites of Canadian plastic surgery centers in the following manner: "[physician name] [province of practice]." RESULTS: A total of 209 websites and 13,838 images were identified and analyzed. Of these images, 12,386 (90%) were female and 1452 (10%) were male patients or models. Although only 20% had a male services page, 62% of all centers offered gynecomastia procedures. The most common procedures targeting men were blepharoplasty (95%), liposuction (93%), and abdominoplasty (93%). The Prairies region had significantly fewer websites with male-only pages compared with all other Canadian regions. CONCLUSIONS: Despite the increase in cosmetic surgery procedures for males, the market for cosmetic surgery procedures targeted towards males remains insignificant. An increase in the advertising of in-demand male cosmetic procedures can allow for a broader consumer market and a subsequent increase in benefits for plastic surgeons.

Extracellular vesicle biomarkers of Alzheimer's disease associated with sub-clinical cognitive decline in late middle age.

INTRODUCTION: Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age-associated cognitive decline. METHODS: This case-control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change. RESULTS: Declining compared to stable individuals showed higher baseline total, p231-, and p181-tau with older age and higher annualized change for p-IR and p-IGF-1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively. DISCUSSION: Combining nEV biomarkers can identify individuals with age-associated cognitive decline.

Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer's disease.

Fluid biomarkers for cognitive impairment have the advantage of being relatively noninvasive and capable of monitoring neuronal and other brain cell health in real time. Biomarkers can predict the onset of dementing illness, but also correlate with cognition in a dynamic way allowing us to follow treatment responses and determine brain recovery. Chronic HIV infection causes cognitive impairment in a subset of individuals suggesting "premature aging." Exosomes are small extracellular vesicles that are shed from all cells. They are important in normal cell-to-cell communication as they contain cellular proteins, mRNA transcripts, and miRNAs. Exosome cargo varies depending on the health of the cell and pathological state; specific proteins/mRNAs and/or miRNAs are present and may serve as biomarkers. Exosomes of variable cellular origin can be isolated from peripheral blood by various methods. Neuron-derived exosomes (NDEs) can be isolated using a precipitation/immunoaffinity approach using antibodies against neuronal cell adhesion molecule L1CAM and the contents queried for central nervous system (CNS) disorders including HIV-associated neurological disorders (HAND) and Alzheimer's disease (AD). As these studies are recent, numerous questions arise including which neuronal proteins are in NDEs and whether their contents differ in different CNS pathologies or with age. In addition, can the NDE cargo predict as well as diagnose cognitive impairment and could exosomal contents be used as therapeutic biomarkers, or theramarkers, of neuronal recovery from effective treatment? This mini-review will show some new data and review recent studies on NDE from individuals with HIV infection and AD. HIV-associated neurocognitive disorders (HAND) are pathologies seen in a subset of individuals with chronic HIV infection. They belong to the spectrum of neurodegenerative diseases that result in death or dysfunction of neurons with similarities to Alzheimer disease (AD) but also distinctive differences (reviewed (Canet et al., Front Cell Neurosci 12: 307, 2018)). Both disorders are difficult to diagnose without neuropsychological testing and both need new biomarkers to judge progression as well as recovery with treatment. Both disorders involve neuroinflammation and several common targets. AD is associated with aging and HIV is thought to initiate premature aging. In HIV infection, amyloid beta (Aß), which is deposited in "plaques" in AD, is soluble and its relevance to HIV-associated cognitive impairment is controversial (Achim et al., J Neuroimmune Pharmacol 4: 190-199, 2009; Rempel and Pulliam, AIDS 19: 127-135, 2005). Aß deposition is required for AD pathological diagnosis, but is not necessarily causative (Barage and Sonawane, Neuropeptides 52: 1-18, 2015; Hardy and Selkoe, Science 297: 353-356, 2002; Morris et al., Acta Neuropathol Commun 2: 135, 2014). Neurofilament light (NF-L) is a surrogate marker in plasma and cerebrospinal fluid (CSF) for neurodegeneration (Abu-Rumeileh et al., Alzheimers Res Ther 10: 3, 2018; Mattsson et al., JAMA Neurol 74: 557-566, 2017) but continues to be a controversial biomarker for both HAND and AD (Gisslen et al., EBioMedicine 3: 135-140, 2016; Kovacs et al., Eur J Neurol 24:1326-e77, 2017; Norgren et al., Brain Res 987: 25-31, 2003; Rolstad et al., J Alzheimers Dis 45: 873-881, 2015; Yilmaz et al., Expert Rev Mol Diagn 17: 761-770, 2017). Blood biomarkers are needed to advance both HAND and AD fields, as blood draws are less costly than neuroimaging and are minimally invasive compared to lumbar punctures required for CSF acquisition. Extracellular vesicles (EVs) are nanoscale membranous vesicles shed from all cells including those of the central nervous system (CNS) and found in all biofluids; they are divided into exosomes (30-150 nm) originating from late endosomes/multivesicular bodies and microvesicles (150-1000 nm) produced through budding of the plasma membrane. Both types of vesicles are implicated in the pathogenesis of neurodegenerative diseases and may provide biomarkers (Bellingham et al., Front Physiol 3: 124, 2012). In this report, we call the vesicles exosomes, since they are the predominant vesicles in our preparations. They are involved in cell-to-cell communication in normal homeostasis and can be carriers of toxic proteins (Aß, tau) (Sardar Sinha et al., Acta Neuropathol 136: 41-56, 2018) shed by cells as waste or actively secreted in a degenerative process (review Gupta and Pulliam, J Neuroinflammation 11: 68, 2014). The idea that exosomes originating from a specific cell can be recovered in the plasma using cellular surface markers of interest is intriguing. Neuron derived exosomes (NDEs) were first described in 2015 and isolated using antibodies against neural cell adhesion molecules NCAM or L1CAM, after total plasma exosome isolation (Fiandaca et al., Alzheimers Dement 11: 600-607 e1, 2015). Characterization of NDEs follows guidelines endorsed by the International Society for Extracellular Vesicles and includes Nanoparticle Tracking Analysis (NTA) to determine EV concentration and average diameter; Western Blots for EV markers; ELISAs for neuronal proteins and transmission EM for visualization (Sun et al., AIDS 31: F9-F17, 2017; Tang et al., FASEB J 30: 3097-106, 2016). This innovative isolation of an exosome sub-population has generated interest in using NDE as biomarkers for neurodegenerative diseases like AD, HAND, traumatic brain injury, posttraumatic stress disorder and more (reviews Agoston et al., Brain Inj 31: 1195-1203, 2017; Gupta and Pulliam, J Neuroinflammation 11: 68, 2014; Hu et al., Cell Death Dis 7: e2481, 2016; Karnati et al., J Neurotrauma, 2018; Osier et al., Mol Neurobiol, 2018). Several biomarkers from plasma NDEs were recently reported by the Pulliam lab to be elevated in general cognitive impairment (Sun et al., AIDS 31: F9-F17, 2017). We review our collective data here on HAND and AD and add to the characterization of plasma NDEs as exciting biomarkers of neurodegeneration.

Machine Learning to Predict the Need for Postmastectomy Radiotherapy after Immediate Breast Reconstruction.

Background: Post mastectomy radiotherapy (PMRT) is an independent predictor of reconstructive complications. PMRT may alter the timing and type of reconstruction recommended. This study aimed to create a machine learning model to predict the probability of requiring PMRT after immediate breast reconstruction (IBR). Methods: In this retrospective study, breast cancer patients who underwent IBR from January 2017 to December 2020 were reviewed and data were collected on 81 preoperative characteristics. Primary outcome was recommendation for PMRT. Four algorithms were compared to maximize performance and clinical utility: logistic regression, elastic net (EN), logistic lasso, and random forest (RF). The cohort was split into a development dataset (75% of cohort for training-validation) and 25% used for the test set. Model performance was evaluated using area under the receiver operating characteristic curve (AUC), precision-recall curves, and calibration plots. Results: In a total of 800 patients, 325 (40.6%) patients were recommended to undergo PMRT. With the training-validation dataset (n = 600), model performance was logistic regression 0.73 AUC [95% confidence interval (CI) 0.65-0.80]; RF 0.77 AUC (95% CI, 0.74-0.81); EN 0.77 AUC (95% CI, 0.73-0.81); logistic lasso 0.76 AUC (95% CI, 0.72-0.80). Without significantly sacrificing performance, 81 predictive factors were reduced to 12 for prediction with the EN method. With the test dataset (n = 200), performance of the EN prediction model was confirmed [0.794 AUC (95% CI, 0.730-0.858)]. Conclusion: A parsimonious accurate machine learning model for predicting PMRT after IBR was developed, tested, and translated into a clinically applicable online calculator for providers and patients.

Adult kitchen-related burn injuries: The impact of COVID-19.

INTRODUCTION: Kitchen-related burn injuries are common and preventable. To limit the spread of COVID-19, public health orders encouraged the public to stay at home which may have led to an increase in kitchen-related burn injuries. OBJECTIVE: To assess adult kitchen-related burns treated in an outpatient setting in general, and especially looking at the impact of the COVID-19 pandemic on the incidence and epidemiology of these burns. METHODS: For this retrospective, population-based study, data were obtained for adult patients who suffered burn injuries resulting in a visit to a Canadian tertiary Burn Clinic between April 2016 and March 2021 specifically looking at demographics, burn etiology, severity and anatomical location and the need for surgery. Separately, we compared the patients before and after the beginning of the COVID-19 pandemic (April 1, 2020). RESULTS: A total of 1380 burn patients were identified. Of these, 38 % (N = 521) sustained a kitchen-related burn. The median patient age was 40 years (range 18-95) and 282 (54.1 %) were female. The most common etiology and location were scald (76.8 %) and anterior arm (28.5 %), respectively. Thirty-two (6.1 %) patients required admission to the Burn Unit and 26 of these had surgeries. Additionally, 72 (13.8 %) patients had surgery as an outpatient. During the COVID-19 pandemic, East Asian patients saw a significant increase in kitchen burns (p < 0.01). CONCLUSION: Over 1/3 of burns at the outpatient burn clinic were kitchen-related. About 94 % of these were treated as outpatient only. The incidence of kitchen-related burns did not change during the COVID-19 pandemic, but we found significant differences in ethnic distribution. These results provide a unique opportunity to focus on communication and education and set up preventative measures.

An Evaluation of the Content of Canadian Plastic Surgery Residency Websites.

Background: Plastic surgery residency program websites are an important source of information to prospective applicants, especially given the ongoing COVID-19 pandemic and resulting suspension of all visiting electives and in-person interviews. This study aimed to analyze the online content of Canadian plastic surgery residency program websites. Methods: The content of all accredited Canadian plastic surgery residency websites was evaluated using 77-point criteria in the following 10 domains: recruitment, faculty, residents, research and education, surgical program, clinical work, benefits and career planning, wellness, environment, and gender of faculty leadership. Results: All accredited Canadian plastic surgery residency programs (n = 13) were identified using Canadian Resident Matching Service and had their dedicated program websites available for analysis. On average, residency program websites obtained a score of 33.5 (standard deviation = 13.7). The majority of programs did not score differently on the criteria by geographical distribution (P > .05) nor by ranking (P > .05). Conclusions: Most Canadian plastic surgery residency program websites are lacking content relevant to prospective applicants. Addressing inadequacies in online content may support programs to inform and recruit strong applicants into residency programs.

Historique: Les sites Web des programmes de résidence en chirurgie plastique sont une source d'information importante pour les candidats potentiels, notamment en contexte de pandémie de COVID-19 et de suspension de tous les séjours pour cours facultatifs et des entrevues en personne. La présente étude visait à analyser le contenu des sites Web des programmes canadiens de résidence en chirurgie plastique. Méthodologie: Les chercheurs ont évalué le contenu de tous les sites Web canadiens de résidence en chirurgie plastique d'après des critères en 77 points dans les dix domaines suivants: recrutement, professeurs, résidents, recherche et formation, programme de chirurgie, travail clinique, avantages sociaux et planification de carrière, bien-être, environnement et genre de la direction des professeurs. Résultats: Les chercheurs ont utilisé le service canadien de jumelage des résidents pour repérer tous les programmes canadiens agréés en chirurgie plastique (n = 13) et ont retenu ceux qui étaient dotés d'un site Web consacré au programme pour en analyser le contenu. En moyenne, ils leur ont attribué un score de 33,5 (ÉT = 13,7). La majorité des programmes n'obtenaient pas de scores différents au critère de la répartition géographique (P > 0,05) ou du classement (P > 0,05). Conclusions: La plupart des sites Web des programmes canadiens de résidence en chirurgie plastique ne contiennent pas d'information pertinente pour les candidats potentiels. Si les programmes connaissent les lacunes de leur contenu en ligne, ils pourront apporter les correctifs nécessaires pour informer de solides candidats et les recruter dans leur programme de résidence.

Entering the Misinformation Age: Quality and Reliability of YouTube for Patient Information on Liposuction.

Background: YouTube is currently the most popular online platform and is increasingly being utilized by patients as a resource on aesthetic surgery. Yet, its content is largely unregulated and this may result in dissemination of unreliable and inaccurate information. The objective of this study was to evaluate the quality and reliability of YouTube liposuction content available to potential patients. Methods: YouTube was screened using the keywords: "liposuction," "lipoplasty," and "body sculpting." The top 50 results for each term were screened for relevance. Videos which met the inclusion criteria were scored using the Global Quality Score (GQS) for educational value and the Journal of the American Medical Association (JAMA) criteria for video reliability. Educational value, reliability, video views, likes, dislikes, duration and publishing date were compared between authorship groups, high/low reliability, and high/low educational value. Results: A total of 150 videos were screened, of which 89 videos met the inclusion criteria. Overall, the videos had low reliability (mean JAMA score = 2.78, SD = 1.15) and low educational value (mean GQS score = 3.55, SD = 1.31). Videos uploaded by physicians accounted for 83.1% percent of included videos and had a higher mean educational value and reliability score than those by patients. Video views, likes, dislikes, comments, popularity, and length were significantly greater in videos with high reliability. Conclusions: To ensure liposuction-seeking patients are appropriately educated and informed, surgeons and their patients may benefit from an analysis of educational quality and reliability of such online content. Surgeons may wish to discuss online sources of information with patients.

Historique : YouTube est actuellement la plateforme la plus populaire en ligne. Les patients l'utilisent de plus en plus comme ressource en chirurgie plastique. Pourtant, son contenu est en grande partie non réglementé, ce qui peut entraîner la diffusion d'information peu fiable et inexacte. La présente étude vise à évaluer la qualité et la fiabilité du contenu de YouTube sur la liposuccion à la disposition de patients éventuels. Méthodologie : Les chercheurs ont fait une recherche dans YouTube à l'aide des mots-clés liposuction, lipoplasty et body sculpting. Ils ont examiné les 50 premiers résultats de chaque terme pour en déterminer la pertinence. Ils ont classé les vidéos qui respectaient les critères d'inclusion d'après le score de qualité globale (SGQ) pour leur valeur éducative et les critères du Journal of the American Medical Association (JAMA) pour la fiabilité des vidéos. Ils ont comparé la valeur éducative, leur fiabilité, le nombre de visionnements, les « J'aime ¼, les « Je n'aime pas ¼, la durée et la date de publication entre groupes d'auteur, la forte et la faible fiabilité et la valeur éducative élevée ou basse. Résultats : Les chercheurs ont visionné 150 vidéos, dont 89 respectaient les critères d'inclusion. Dans l'ensemble, elles avaient une faible fiabilité (score JAMA moyen = 2.78, ÉT = 1.15) et une faible valeur éducative (SQG moyen = 3.55, ÉT = 1.31). Les vidéos téléversées par des médecins formaient 83,1% du contenu et présentaient une valeur éducative moyenne et un score de fiabilité plus élevés que celles des patients. Les visionnements, les « J'aime ¼, les « Je n'aime pas ¼, les commentaires, la popularité et la durée étaient beaucoup plus élevés lorsque les vidéos avaient une forte viabilité. Conclusions : Pour que les patients qui veulent subir une liposuccion reçoivent la bonne information, les chercheurs et leurs patients peuvent profiter d'une analyse de la qualité et de la fiabilité du contenu en ligne. Les chirurgiens pourraient souhaiter parler des sources d'information en ligne avec leurs patients.

An Analysis of Racial Diversity in the Breast Reconstruction and Aesthetic Surgery Literature.

Background: Racial disparities in the visual representation of patients in the plastic surgery literature can contribute to health inequities. This study evaluates racial diversity in photographs published in the aesthetic and breast reconstruction literature. Methods: A photogrammetric analysis of plastic surgery journals from the USA, Canada, and Europe was performed. Color photographs depicting human skin, pertaining to breast reconstruction and aesthetic surgery in 2000, 2010, and 2020, were categorized as White (1-3) or non-White (4-6) based on the Fitzpatrick scale. Results: All journals demonstrated significantly more White skin images than non-White for all procedures (P < 0.05) except blepharoplasty and rhinoplasty. Blepharoplasty was the only procedure with more non-White images (P = 0.02). When examining USA journals, significant differences were not found in blepharoplasty, rhinoplasty, and male chest surgery. European journals published a greater proportion of non-White images than USA journals (P < 0.0001). There was a decreasing rate of change in diversity with 15.5% of images being non-White in 2000, 32.7% in 2010, and 40.7% in 2020 (P < 0.01). Percentage of non-White images varied by geographical region and ranged from 3.6% in Oceania to 93.5% in Asia (P < 0.01). Conclusions: Diversity of patient populations depicted in plastic surgery literature has increased over the past two decades. Despite this improvement, the racial diversity seen in photographs published in the literature does not adequately reflect this demographic for aesthetic and breast procedures. Equitable visual representation may promote cultural competency and improve care for the populations we serve.

Need for Speed: Investigating Publication Times and Impact Factors of Plastic Surgery Journals.

BACKGROUND: Prolonged publishing time in scientific journals can be discouraging for researchers because earlier publication can mean a higher h-index and more academic opportunities. In this study, we evaluated the publication time for articles in plastic surgery journals compared with journals in surgery and medicine. We also assessed correlations between publication speed and journal impact factors (IFs). METHODS: The overall indexes of all plastic surgery journals were compared with journals in the discipline of surgery and medicine. In addition, we evaluated original articles published in all plastic surgical journals and the highest-ranking journals from various surgical subspecialties listed in the 2018 Journal Citation Report, assessing the time intervals from submission to publication, submission to acceptance, and acceptance to publication. Correlation between time interval and journal IF were analyzed. RESULTS: A total of 18 plastic surgery journals were compared with 210 surgical journals. Our study found that the IFs of journals significantly affect submission-to-acceptance times of the articles (P < 0.05, Wilcoxon test). The median submission-to-publication time for all plastic surgery and all surgical journals was 29.7 weeks (IQR, 12.1 and 35.8) and 22.1 days (IQR,18.8 and 36.8), respectively. CONCLUSIONS: There is a significant submission to publication time lag in plastic surgery journals when compared with other nonplastic-surgery journals. There was a positive correlation between submission-to publication time and IF for plastic surgery journals but a negative correlation for surgery journals (Spearman Correlation). In the last 14 years, plastic surgery journals have remained slow in publishing articles.

The State of Diversity in Academic Plastic Surgery Faculty across North America.

BACKGROUND: Gender and racial disparity is prevalent in all surgical subspecialties with women and racial groups historically underrepresented in academic plastic surgery. This study evaluated gender and racial profiles of academic plastic surgery faculty in North America and correlated both with research productivity and its effect on academic ranks of faculty in plastic surgery. METHODS: In this cross-sectional study, we compiled a list of accredited medical schools that offer plastic surgery training for residency. Data were collected on demographics, academic rank, and research output using the Doximity, LinkedIn, and Scopus databases. Data analyses were performed with a Mann-Whitney U test and a Kruskal-Wallis test. RESULTS: Women who were black, indigenous, and/or other color occupied only 6.25% of plastic surgery faculty leadership positions in North America. There are more women and underrepresented minorities in leadership positions in Canada, when compared with the USA, relative to each country's demographic. In both countries, women and underrepresented minority plastic surgeons had fewer publications, citations, and years of active research. Interestingly, having women in leadership positions was associated with a higher number of women faculty members. CONCLUSIONS: Gender and racial disparity exist in academic plastic surgery in North America. Several changes are required in order for women and underrepresented minorities in medicine to have an equal chance at career advancement. Better representation and diverse leadership have the potential to bring about equity, diversity, and inclusion in academic plastic surgery.

How Comprehensive Are Canadian Plastic Surgery Fellowship Websites?

Background Online fellowship program websites are more commonly becoming the primary information resource used by prospective applicants. This study aimed to analyze the online content of Canadian plastic surgery fellowship program websites.  Methods The content of all accredited Canadian Plastic Surgery fellowship program websites was evaluated using a 75-point criterion in the following ten domains: recruitment, faculty, residents/fellows, research and education, surgical program, clinical work, benefits, and career planning, wellness, environment and gender of faculty leadership.  Results On average, fellowship program websites obtained a score of 29.9 (SD=12.6). No correlation was detected between program websites and location (P > 0.05) nor by ranking (P > 0.05).  Conclusions Most Canadian plastic surgery fellowship program websites lacked content relevant to prospective applicants. More comprehensive fellowship program websites may be of benefit to prospective applicants and the programs.

Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in Communities Study.

We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities-Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3ß) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3ß, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression.

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ2 = 9.275, p = 0.026), NF-κB (χ2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα) (χ2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

Altered Levels of Toll-Like Receptors in Circulating Extracellular Vesicles in Multiple Sclerosis.

Extracellular vesicles (EVs) are involved in inter-cellular communication and their cargo may provide prognostic/diagnostic biomarkers. To discover EV-associated biomarkers for Multiple Sclerosis (MS), we used an immune marker array to identify surface proteins on circulating EVs that differ between MS patients and controls (n = 3 each). We identified toll-like receptor-3 (TLR3) as a potential target for further validation. We utilized prospectively collected serum from relapsing-remitting MS patients (n = 18) and controls (n = 16) and confirmed lower concentration of TLR3 and higher concentration of mechanistically related TLR4 in MS EVs compared to controls. Future studies may further evaluate the utility of EV-associated TLRs as MS biomarkers and uncover their mechanistic significance.

Extracellular vesicles reveal abnormalities in neuronal iron metabolism in restless legs syndrome.

STUDY OBJECTIVES: Determine abnormalities in levels of iron-management proteins in neuronal origin-enriched extracellular vesicles (nEVs) in restless legs syndrome (RLS). METHODS: We used immunoprecipitation for neuronal marker L1CAM to isolate nEVs from the serum of 20 participants with RLS from a study including magnetic resonance imaging (MRI) determinations of iron deposition in the substantia nigra and hematologic parameters and 28 age- and sex-matched Controls. RESULTS: RLS compared with Control participants showed higher levels of nEV total ferritin but similar levels of transferrin receptor and ferroportin. Western blot analysis showed that heavy- but not light-chain ferritin was increased in nEVs of RLS compared with Control participants. In RLS but not Control participants, nEV total ferritin was positively correlated with systemic iron parameters; the two groups also differed in the relation of nEV total ferritin to MRI measures of iron deposition in substantia nigra. CONCLUSIONS: Given the neuronal origin and diversity of EV cargo, nEVs provide an important platform for exploring the underlying pathophysiology and possible biomarkers of RLS.