The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. METHODS: Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. RESULTS: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). CONCLUSION: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Anion Sensing through Redox-Modulated Fluorescent Halogen Bonding and Hydrogen Bonding Hosts.

Anion sensing via either optical or electrochemical readouts has separately received enormous attention, however, a judicious combination of the advantages of both modalities remains unexplored. Toward this goal, we herein disclose a series of novel, redox-active, fluorescent, halogen bonding (XB) and hydrogen bonding (HB) BODIPY-based anion sensors, wherein the introduction of a ferrocene motif induces remarkable changes in the fluorescence response. Extensive fluorescence anion titration, lifetime and electrochemical studies reveal anion binding-induced emission modulation through intramolecular photoinduced electron transfer (PET), the magnitude of which is dependent on the nature of both the XB/HB donor and anion. Impressively, the XB sensor outperformed its HB congener in terms of anion binding strength and fluorescence switching magnitude, displaying significant fluorescence turn-OFF upon anion binding. In contrast, redox-inactive control receptors display a turn-ON response, highlighting the pronounced impact of the introduction of the redox-active ferrocene on the optical sensing performance. Additionally, the redox-active ferrocene motif also serves as an electrochemical reporter group, enabling voltammetric anion sensing in competitive solvents. The combined advantages of both sensing modalities were further exploited in a novel, proof-of-principle, fluorescence spectroelectrochemical anion sensing approach, enabling simultaneous and sensitive read out of optical and electrochemical responses in multiple oxidation states and at very low receptor concentration.

Ultrafast Biomarker Quantification through Reagentless Capacitive Kinetics.

We introduce a facile assessment of binding kinetics at bioreceptive redox-active interfaces as a means of quantifying target proteins. This is achieved by monitoring the redox capacitance (Cr) of a receptor-modified conductive polymer interface under continuous flow. Exemplified with the quantification of C-reactive protein (CRP), capacitance analyses resolve both the association and dissociation regimes in real-time. Significantly, the rate of electrochemical signal change within the association regime is a sensitive function of target concentration, enabling marker assaying down to picomolar levels, comparable to end-point assays, in 15 s. This reagentless proof-of-principle methodology is envisioned to be widely applicable to the facile quantification of a range of other pertinent, clinically relevant targets.

Alternating Magnetic Field-Promoted Nanoparticle Mixing: The On-Chip Immunocapture of Serum Neuronal Exosomes for Parkinson's Disease Diagnostics.

The analysis of cargo proteins in exosome subpopulations has considerable value in diagnostics but a translatable impact has been limited by lengthy or complex exosome extraction protocols. We describe herein a scalable, fast, and low-cost exosome extraction using an alternating (AC) magnetic field to support the dynamic mixing of antibody-coated magnetic beads (MBs) with serum samples within 3D-printed microfluidic chips. Zwitterionic polymer-coated MBs are, specifically, magnetically agitated and support ultraclean exosome capture efficiencies >70% from <50 µL of neat serum in 30 min. Applied herein to the immunocapture of neuronal exosomes using anti-L1CAM antibodies, prior to the array-based assaying of α-synuclein (α-syn) content by a standard duplex electrochemical sandwich ELISA, sub pg/mL detection was possible with an excellent coefficient of variation and a sample-to-answer time of ∼75 min. The high performance and semiautomation of this approach hold promise in underpinning low-cost Parkinson's disease diagnostics and is of value in exosomal biomarker analyses more generally.

Impact of Alignment and Alignment Correction on Outcomes Following Robotic Medial Unicompartmental Knee Arthroplasty.

BACKGROUND: The purpose of this study was to retrospectively examine the relationship between preoperative and postoperative alignment in robotic unicompartmental knee arthroplasty (UKA) and postoperative patient-reported outcome measures. METHODS: A retrospective review of 374 patients who underwent robotic-assisted UKA was conducted. Patient demographics, history, and preoperative and postoperative Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scores were obtained via chart review. Average follow-up period was 2.4 years (range: 0.4 to 4.5 years) to chart review and 9.5 months (range: 6 to 48 months) to latest KOOS-JR. Preoperative and postoperative robotically-measured knee alignment was obtained from operative reports. Incidence of conversion to total knee arthroplasty (TKA) was determined by review of a health information exchange tool. RESULTS: Multivariate regressions showed no statistically significant relationship between preoperative alignment, postoperative alignment, or degrees of alignment correction and change in KOOS-JR score or achievement of KOOS-JR minimal clinically important difference (MCID) (P > .05). Patients who had >8 degrees of postoperative varus alignment had on average a 20% lower achievement of KOOS-JR MCID compared to patients who had <8 degrees of postoperative varus alignment; however, this difference was not statistically significant (P > .05). There were 3 patients who required conversion to TKA in the follow-up period, with no significant relationship to alignment variables (P > .05). CONCLUSION: There was no significant difference in KOOS-JR change for those patients who had a larger or smaller degree of deformity correction, and correction did not predict MCID achievement.

The AAHKS Clinical Research Award: Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial.

BACKGROUND: Intravenous dexamethasone has been shown to reduce pain in total joint arthroplasty. This double-blind, randomized, placebo-controlled trial investigated the postoperative effects and safety of oral dexamethasone as a potential augment to multimodal pain management in outpatient knee arthroplasty. METHODS: The authors prospectively randomized 109 consecutive patients undergoing primary total knee arthroplasty. Patients assigned to Group A (57 patients) received 4 mg of dexamethasone by mouth twice per day starting postoperative day (POD) 1 for 4 days and those assigned to Group B received placebo capsules. All healthcare professionals and patients were blinded to group allocation. The primary outcome was defined as postoperative pain scores. Secondary outcomes included 90-day postoperative complications, nausea and vomiting, daily opioid usage, assistance for ambulation, difficulty sleeping, and early patient reported outcomes. Demographics were similar between groups. RESULTS: The patients who received dexamethasone had a statistically significant decrease in VAS scores when averaging POD 1 to 4 (P = .01). The average VAS scores among individual days were significantly lower with dexamethasone on POD 2, 3, and 4. While taking dexamethasone, morning and mid-day VAS scores were significantly lower. There was no difference between the groups with opioid use, nausea or vomiting, 90-day complications, ability to walk with/without assistance, difficulty sleeping, and early patient reported outcomes. CONCLUSION: This double-blind, randomized, placebo-controlled trial demonstrated that oral dexamethasone following primary total knee arthroplasty can reduce postoperative pain. This may be a beneficial option in ambulatory surgery where intravenous limitations exist, but larger series are needed to further evaluate the safety profile in this population.

Engineered Binding Microenvironments in Halogen Bonding Polymers for Enhanced Anion Sensing.

Mimicking Nature's polymeric protein architectures by designing hosts with binding cavities screened from bulk solvent is a promising approach to achieving anion recognition in competitive media. Accomplishing this, however, can be synthetically demanding. Herein we present a synthetically tractable approach, by directly incorporating potent supramolecular anion-receptive motifs into a polymeric scaffold, tuneable through a judicious selection of the co-monomer. A comprehensive analysis of anion recognition and sensing is demonstrated with redox-active, halogen bonding polymeric hosts. Notably, the polymeric hosts consistently outperform their monomeric analogues, with especially large halide binding enhancements of ca. 50-fold observed in aqueous-organic solvent mixtures. These binding enhancements are rationalised by the generation and presentation of low dielectric constant binding microenvironments from which there is appreciable solvent exclusion.

Redox-Switchable Chalcogen Bonding for Anion Recognition and Sensing.

Inspired by the success of its related sigma-hole congener halogen bonding (XB), chalcogen bonding (ChB) is emerging as a powerful noncovalent interaction with a plethora of applications in supramolecular chemistry and beyond. Despite its increasing importance, the judicious modulation of ChB donor strength remains a formidable challenge. Herein, we present, for the first time, the reversible and large-scale modulation of ChB potency by electrochemical redox control. This is exemplified by both the switching-ON of anion recognition via ChB oxidative activation of a novel bis(ferrocenyltellurotriazole) anion host and switching-OFF reductive ChB deactivation of anion binding potency with a telluroviologen receptor. The direct linking of the redox-active center and ChB receptor donor sites enables strong coupling, which is reflected by up to a remarkable 3 orders of magnitude modulation of anion binding strength. This is demonstrated through large voltammetric perturbations of the respective receptor ferrocene and viologen redox couples, enabling, for the first time, ChB-mediated electrochemical anion sensing. The sensors not only display significant anion-binding-induced electrochemical responses in competitive aqueous-organic solvent systems but can compete with, or even outperform similar, highly potent XB and HB sensors. These observations serve to highlight a unique (redox) tunability of ChB and pave the way for further exploration of the reversible (redox) modulation of ChB in a wide range of applications, including anion sensors as well as molecular switches and machines.

A Quantification of Target Protein Biomarkers in Complex Media by Faradaic Shotgun Tagging.

The progressive emergence of protein biomarkers promises a revolution in the healthcare industry and a shift of focus from disease management to much earlier intervention. Here, we introduce a facile shotgun tagging of ensemble proteins in clinically relevant media prior to specific target capture at antibody-modified electrodes. This facilitates a convenient voltammetric quantification of markers down to sub-pg/mL levels and across several orders of concentration. A translation of the methodology to an automated microfluidic platform enables marker quantification from 25 µL of sample in less than 15 min, demonstrated here with a simultaneous assaying of CRP and cardiac troponin I (cTnI). The assays show a good correlation with a standard immunoassay when applied to real patient serum samples. The platform is simple, generic, highly sensitive and requires no secondary labeling/binding or amplification.

Electrochemical Anion Sensing: Supramolecular Approaches.

Anions play a vital role in a broad range of environmental, technological, and physiological processes, making their detection/quantification valuable. Electroanalytical sensors offer much to the selective, sensitive, cheap, portable, and real-time analysis of anion presence where suitable combinations of selective (noncovalent) recognition and transduction can be integrated. Spurred on by significant developments in anion supramolecular chemistry, electrochemical anion sensing has received considerable attention in the past two decades. In this review, we provide a detailed overview of all electroanalytical techniques that have been used for this purpose, including voltammetric, impedimetric, capacititive, and potentiometric methods. We will confine our discussion to sensors that are based on synthetic anion receptors with a specific focus on reversible, noncovalent interactions, in particular, hydrogen- and halogen-bonding. Apart from their sensory properties, we will also discuss how electrochemical techniques can be used to study anion recognition processes (e.g., binding constant determination) and will furthermore provide a detailed outlook over future efforts and promising new avenues in this field.

Antifouling Strategies for Selective In Vitro and In Vivo Sensing.

The ability to fabricate sensory systems capable of highly selective operation in complex fluid will undoubtedly underpin key future developments in healthcare. However, the abundance of (bio)molecules in these samples can significantly impede performance at the transducing interface where nonspecific adsorption (fouling) can both block specific signal (reducing sensitivity) and greatly reduce assay specificity. Herein, we aim to provide a comprehensive review discussing concepts and recent advances in the construction of antifouling sensors that are, through the use of chemical, physical, or biological engineering, capable of operating in complex sample matrix (e.g., serum). We specifically highlight a range of molecular approaches to the construction of solid sensory interfaces (planar and nanoparticulate) and their characterization and performance in diverse in vitro and in vivo analyte (e.g., proteins, nucleic acids, cells, neuronal transmitters) detection applications via derived selective optical or electrochemical strategies. We specifically highlight those sensors that are capable of detection in complex media or those based on novel architectures/approaches. Finally, we provide perspectives on future developments in this rapidly evolving field.

Ultrasound evaluations and guided procedures of the painful joint arthroplasty.

The purpose of this article is to describe the use of ultrasound for the diagnosis and treatment of painful joint arthroplasty. Ultrasound plays a crucial role in the diagnosis of the painful joint arthroplasty, especially given its unique dynamic capabilities, convenience, and high resolution. Ultrasound guidance is also instrumental for procedures in both diagnosing and in select cases, treating the painful joint arthroplasty. Topics to be discussed in this article include trends in arthroplasty placement, benefits of the use of ultrasound overall, and ultrasound evaluation of periprosthetic joint infections. We will also review the sonographic findings with dissociated/displaced components and adverse reaction to metallic debris including metallosis, trunnionosis, and metal-on-metal pseudotumors. Additionally, we will discuss ultrasound evaluation of tendon pathologies with arthroplasties, including dynamic maneuvers to evaluate for tendon impingement/snapping. Finally, we will cover ultrasound-guided joint arthroplasty injection indications and precautions. KEY POINTS: • Ultrasound is preferred over MRI in patients with joint arthroplasty and plays a crucial role in diagnosis, especially given its unique dynamic capabilities, convenience and high resolution. • It is especially beneficial for US-guided aspiration in periprosthetic joint infections; effectively used to evaluate periprosthetic fluid collections, facilitating differentiation between abscesses and aseptic collections, and tracking sinus tracts. • Recently, the diagnosis of periprosthetic joint infections has shifted focus to biomarkers in the periprosthetic fluid, specifically α-defensin, which has a high sensitivity and specificity for diagnosing infection. • Cutibacterium acnes is a major pathogen responsible for shoulder arthroplasty infections, often presenting with normal laboratory values and since slow growing, must be kept for a minimum of 14 days.

Changes in Patient Reported Outcome Measure Scores From Initial Presentation to Day-of-Surgery in Patients Undergoing Hip and Knee Arthroplasty.

BACKGROUND: It is not well understood how patient reported outcome measures (PROMs) change from initial presentation to day-of-surgery (DOS). This study sought to quantify preoperative PROM changes for hip and knee arthroplasty patients. METHODS: A retrospective review was performed on primary total hip, total knee, and partial knee arthroplasty patients from October 2020 through January 2021. Trends in preoperative Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), Hip Disability and Osteoarthritis Outcome Score for Joint Replacement (HOOS-JR), and Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scores were compared using scores at initial presentation in the ambulatory clinic and at a time near the date-of-surgery. A total of 497 patients possessed 2 preoperative PROMIS-PF (497/497), HOOS-JR (152/497), or KOOS-JR (258/497) surveys. RESULTS: There was no significant statistical difference in mean PROM scores between initial presentation and DOS PROMIS-PF or HOOS-JR scores. Only KOOS-JR demonstrated a significant statistical difference of 2 ± 14 (P = .002) when comparing initial versus preoperative scores. Partial knee arthroplasty patients saw a strong positive correlation (r = 0.77) between initial PROMIS-PF and DOS scores. However, mean absolute value changes on an individual level were 4 ± 4, 11 ± 39, and 11 ± 10 for PROMIS-PF, HOOS-JR, and KOOS-JR, respectively, indicating the presence of meaningful patient-level score changes as based on previously published anchor-based minimal clinically important differences. CONCLUSION: PROMs collected during the preoperative period demonstrated wide variability at an individual level, but not at a population level. Collection at both time points may be necessary in order to understand the clinical impact of surgery on these patients.

Comparison of Postoperative Instability and Acetabular Cup Positioning in Robotic-Assisted Versus Traditional Total Hip Arthroplasty.

BACKGROUND: Robotic-assisted total hip arthroplasty (R-THA) affords precision yet uncertain clinical benefits. This study compares dislocation rates and related revisions between R-THA and manual total hip arthroplasty (M-THA). Secondarily we evaluated cup position, patient-reported outcome measures (PROMs), and postoperative complications. METHODS: A three-surgeon cohort study was conducted on 2247 consecutive patients (1724 M-THA and 523 R-THA) who received a primary THA between January 2014 and June 2020 at a single hospital. Demographics, PROMs, emergency department visits, readmissions, and 90-day complications were collected via the Michigan Arthroplasty Registry Collaborative Quality Initiative. Chart review yielded instability occurrence with an average follow-up of 4 years. Multivariate regression analysis was performed, and a sample of 368 radiographs, including all dislocations, were assessed. RESULTS: There were significantly lower rates of dislocation in R-THA (0.6%) vs M-THA (2.5%; Multivariate odds ratio 3.74, P < .046). All cases of unstable R-THA were successfully treated conservatively, whereas 46% of unstable M-THA were revised for recurrent instability. Cup anteversion (25.6° ± 5.4° R-THA vs 20.6° ± 7.6° M-THA) was greater, and cup inclination (42.5° ± 5.3° R-THA vs 47.0° ± 6.7° M-THA) was lower in the R-THA group (P < .05). No significant differences were noted for demographics, PROMs, or other complications (P > .05). CONCLUSION: R-THA resulted in less than one-fourth the dislocation rate compared to M-THA and no revision for instability. It was associated with no difference in PROMs or other early complications. The influence of R-THA on stability goes beyond simply cup positioning and deserves further study.

Delayed debridement of open tibia fractures beyond 24 and 48 h does not appear to increase infection and reoperation risk.

PURPOSE: Surgical debridement is critical to the treatment of open tibia fractures, although the effects of delayed debridement have not been well-established. Other factors such as Gustilo-Anderson type, prompt initiation of antibiotics, and time to definitive closure may be more predictive of infection than time to surgery. We sought to determine the effect of a prolonged delay to surgical debridement with respect to infection and reoperation rates for open tibia fractures. METHODS: All open diaphyseal tibia fractures with > 12-week follow-up were evaluated. Patient demographics, Gustilo-Anderson type, and rates of deep infection and all-cause reoperation were recorded. Patients were divided into 3 groups based on time to surgery: early (< 24 h), delayed (24-48 h), and late (> 48 h). Univariate and multivariate analyses were performed to evaluate the relationship between time to surgery, fracture type, infection, and reoperation. RESULTS: In total, 96 open tibia fractures with average follow-up of 59.3 weeks and infection rate of 13.5% were included. Infection rates for the early, delayed, and late groups were 13.3%, 17.2%, and 9.1%, respectively (p = 0.70). Reoperation rates for the early, delayed, and late groups were 29.8%, 31.0%, and 22.7%, respectively (p = 0.80). The groups did not vary in proportion of Gustilo-Anderson fracture types; infection rates between Gustilo-Anderson types were similar (p = 0.57). Type IIIA-C fractures required more reoperations than other fracture types (p = 0.01). CONCLUSION: Delayed surgical debridement of open tibia fractures did not result in greater rates of infection or reoperation. Gustilo-Anderson classification was more predictive of reoperation, with Type IIIA-C injuries having a significantly higher reoperation rate.

Continuous and Polarization-Tuned Redox Capacitive Anion Sensing at Electroactive Interfaces.

Continuous, real-time ion sensing is of great value across various environmental and medical scenarios but remains underdeveloped. Herein, we demonstrate the potential of redox capacitance spectroscopy as a sensitive and highly adaptable ion sensing methodology, exemplified by the continuous flow sensing of anions at redox-active halogen bonding ferrocenylisophthalamide self-assembled monolayers. Upon anion binding, the redox distribution of the electroactive interface, and its associated redox capacitance, are reversibly modulated, providing a simple and direct sensory readout. Importantly, the redox capacitance can be monitored at a freely chosen, constant electrode polarization, providing a facile means of tuning both the sensor analytical performance and the anion binding affinity, by up to 1 order of magnitude. In surpassing standard voltammetric methods in terms of analytical performance and adaptability, these findings pave the way for the development of highly sensitive and uniquely tunable ion sensors. More generally, this methodology also serves as a powerful and unprecedented means of simultaneously modulating and monitoring the thermodynamics and kinetics of host-guest interactions at redox-active interfaces.

Open Circuit Potential as a Tool for the Assessment of Binding Kinetics and Reagentless Protein Quantitation.

A microfluidic open circuit potential label-free protein assay was developed for the reagentless quantification of C-reactive protein (CRP), a model protein target, and further utilized to assess target-receptor binding kinetics. Generated sensors have very high baseline stabilities (<1% change in 100 min) and high levels of selectivity in complex media. Real-time assays are fast (<20 min), of high sensitivity (1 ng/mL limit of detection for CRP in serum), and resolve kinetic and thermodynamic characteristics that correlate well with those resolved optically. The assay shows excellent correlation with an enzyme-linked immunosorbent assay analysis of patient samples. The methodology has value in potentially underpinning a low-cost, rapid, and sensitive single-step biomarker quantification.

Solvent Effects in Halogen and Hydrogen Bonding Mediated Electrochemical Anion Sensing in Aqueous Solution and at Interfaces.

Sensing anionic species in competitive aqueous media is a well-recognised challenge to long-term applications across a multitude of fields. Herein, we report a comprehensive investigation of the electrochemical anion sensing performance of novel halogen bonding (XB) and hydrogen bonding (HB) bis-ferrocene-(iodo)triazole receptors in solution and at self-assembled monolayers (SAMs), in a range of increasingly competitive aqueous organic solvent media (ACN/H2 O). In solution, the XB sensor notably outperforms the HB sensor, with substantial anion recognition induced cathodic voltammetric responses of the ferrocene/ferrocenium redox couple persisting even in highly competitive aqueous solvent media of 20 % water content. The response to halides, in particular, shows a markedly lower sensitivity to increasing water content associated with a unique halide selectivity at unprecedented levels of solvent polarity. The HB sensor, in contrast, generally displayed a preference towards oxoanions. A significant surface-enhancement effect was observed for both XB/HB receptive films in all solvent systems, whereby the HB sensor generally displayed larger responses towards oxoanions than its halogen bonding analogue.

Real-time Voltammetric Anion Sensing Under Flow.

The development of real-life applicable ion sensors, in particular those capable of repeat use and long-term monitoring, remains a formidable challenge. Herein, we demonstrate, in a proof-of-concept, the real-time voltammetric sensing of anions under continuous flow in a 3D-printed microfluidic system. Electro-active anion receptive halogen bonding (XB) and hydrogen bonding (HB) ferrocene-isophthalamide-(iodo)triazole films were employed as exemplary sensory interfaces. Upon exposure to anions, the cathodic perturbations of the ferrocene redox-transducer are monitored by repeat square-wave voltammetry (SWV) cycling and peak fitting of the voltammograms by a custom-written MATLAB script. This enables the facile and automated data processing of thousands of SW scans and is associated with an over one order-of-magnitude improvement in limits of detection. In addition, this improved analysis enables tuning of the measurement parameters such that high temporal resolution can be achieved. More generally, this new flow methodology is extendable to a variety of other analytes, including cations, and presents an important step towards translation of voltammetric ion sensors from laboratory to real-world applications.

Validation of α-Synuclein in L1CAM-Immunocaptured Exosomes as a Biomarker for the Stratification of Parkinsonian Syndromes.

BACKGROUND: Parkinson's disease is characterized by intraneuronal α-synuclein aggregation. Currently there is no α-synuclein-based blood test in clinical practice. OBJECTIVES: Our aim was to assess by means of further testing and analysis whether α-synuclein measurements in serum L1CAM-immunocaptured exosomes can differentiate Parkinson's disease from related movement disorders. METHODS: We used poly(carboxybetaine-methacrylate)-coated magnetic beads to isolate L1CAM-positive exosomes and triplexed electrochemiluminescence to measure exosomal α-synuclein, clusterin, and syntenin-1 from 267 serum samples. Combined analysis of our current and previously published data from the Oxford, Kiel, Brescia, and PROSPECT cohorts consisting of individuals (total n = 735) with Parkinson's disease (n = 290), multiple system atrophy (MSA, n = 50), progressive supranuclear palsy (n = 116), corticobasal syndrome (n = 88), and healthy controls (n = 191) was done using 2-stage (training vs validation) receiver operating characteristic analysis. RESULTS: We established that α-synuclein level in L1CAM-immunocaptured exosomes above 14 pg/mL is a robust biomarker across cohorts that distinguishes Parkinson's disease from MSA (AUC, 0.90 vs 0.98) or 4-repeat tauopathies (AUC, 0.93 vs 0.94). We confirmed that exosomal clusterin is elevated in subjects with 4-repeat tauopathy, and when combined with α-synuclein, it improved the performance of the assay in differentiating Parkinson's disease from 4-repeat tauopathies to AUC, 0.98 versus 0.99. Correction for the generic exosomal protein syntenin-1 did not consistently improve the performance of the assay. CONCLUSIONS: α-Synuclein and clusterin in L1CAM-immunocaptured serum exosomes is a validated blood test for the molecular stratification of neuronal α-synucleinopathy (ie, Lewy body pathology) versus phenotypically related neurodegenerative movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.