An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm.

BACKGROUND: Blepharospasm is treated with botulinum toxin, but obtaining satisfactory results is sometimes challenging. OBJECTIVE: The aim is to conduct an exploratory trial of oral dipraglurant for blepharospasm. METHODS: This study was an exploratory, phase 2a, randomized, double-blind, placebo-controlled trial of 15 participants who were assigned to receive a placebo or dipraglurant (50 or 100 mg) and assessed over 2 days, 1 and 2 hours following dosing. Outcome measures included multiple scales rated by clinicians or participants, digital video, and a wearable sensor. RESULTS: Dipraglurant was well tolerated, with no obvious impact on any of the measurement outcomes. Power analyses suggested fewer subjects would be required for studies using a within-subject versus independent group design, especially for certain measures. Some outcome measures appeared more suitable than others. CONCLUSION: Although dipraglurant appeared well tolerated, it did not produce a trend for clinical benefit. The results provide valuable information for planning further trials in blepharospasm. © 2024 International Parkinson and Movement Disorder Society.

Interrater reliability of motor severity scales for hemifacial spasm.

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants' motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee's scale), clinical grading of spasm intensity (Chen's scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc's scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from "poor" to "moderate"; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee's, Chen's, and Tunc's scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc's scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc's scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

Abnormal Neural Responses During Reflexive Blinking in Blepharospasm: An Event-Related Functional MRI Study.

BACKGROUND: The neurophysiological disruptions underlying blepharospasm, a disabling movement disorder characterized by increased blinking and involuntary muscle spasms of the eyelid, remain poorly understood. OBJECTIVE: To investigate the neural substrates underlying reflexive blinking in blepharospasm patients compared to healthy controls using simultaneous functional MRI and surface electromyography. METHODS: Fifteen blepharospasm patients and 15 healthy controls were recruited. Randomly timed air puffs to the left eye were used to induce reflexive eye blinks during two 8-minute functional MRI scans. Continuous surface electromyography and video recordings were used to monitor blink responses. Imaging data were analyzed using an event-related design. RESULTS: Fourteen blepharospasm patients (10 female; 61.6 ± 8.0 years) and 15 controls (11 female; 60.9 ± 5.5 years) were included in the final analysis. Reflexive eye blinks in controls were associated with activation of the right hippocampus and in patients with activation of the left caudate nucleus. Reflexive blinks in blepharospasm patients showed increased activation in the right postcentral gyrus and precuneus, left precentral gyrus, and left occipital cortex compared to controls. Dystonia severity negatively correlated with activity in the left occipital cortex, and disease duration negatively correlated with reflexive-blink activity in the cerebellum. CONCLUSIONS: Reflexive blinking in blepharospasm is associated with increased activation in the caudate nucleus and sensorimotor cortices, suggesting a loss of inhibition within the sensorimotor corticobasal ganglia network. The association between decreasing neural response during reflexive blinking in the cerebellum with disease duration suggests an adaptive role. © 2020 International Parkinson and Movement Disorder Society.

Expanded Utility of Human Acellular Vessel in Hemodialysis Access Surgery and Arterial Aneurysm Repair.

Vascular access is essential for hemodialysis (HD) in patients with end-stage renal disease (ESRD). When the standard of care arteriovenous fistula (AVF) is limited, secondary to aneurysmal degeneration, trauma, and thrombus, interposition grafting is a reasonable reconstruction approach. As these grafts and comorbidities place ESRD patients at sustained risk of complications, reconstructions with regenerative medicine biologic conduits hold promise in improving safety and efficacy. Here, a biocompatible human acellular vessel (HAV) is our conduit of interest. With United States Food and Drug Administration use authorization under the Expanded Access Program, we report three cases of complex vascular access surgery with four aneurysm repairs using HAV. Patient selection focused on meeting unmet needs for those without adequate care alternatives, including active access and endoprosthetic stent graft infections, right heart failure due to high-output AVF, and arterial and access outflow aneurysms. In this high-risk expanded access population, operative technical success and interval success for patients given their inherent comorbidities, offer potential expanded utility of HAV in HD access surgery and arterial aneurysm repair.

Endovascular approach to thrombosed limb of aortoiliac endoprosthetic stent graft following abdominal endovascular aneurysm repair.

The increasing use of endovascular aneurysm repair to treat abdominal aortic aneurysms has mandated solutions to the limitations of this operation, including the requirement for additional procedures. A 64-year-old man had presented with symptomatic thrombosis of the left iliac limb after endovascular aneurysm repair. We have reported the use of an innovative endovascular repair for our patient.

Correlating Perceptual Voice Quality in Adductor Spasmodic Dysphonia With Computer Vision Assessment of Glottal Geometry Dynamics.

PURPOSE: This study examined the relationship between voice quality and glottal geometry dynamics in patients with adductor spasmodic dysphonia (ADSD). METHOD: An objective computer vision and machine learning system was developed to extract glottal geometry dynamics from nasolaryngoscopic video recordings for 78 patients with ADSD. General regression models were used to examine the relationship between overall voice quality and 15 variables that capture glottal geometry dynamics derived from the computer vision system. Two experts in ADSD independently rated voice quality for two separate voice tasks for every patient, yielding four different voice quality rating models. RESULTS: All four of the regression models exhibited positive correlations with clinical assessments of voice quality (R 2s = .30-.34, Spearman rho = .55-.61, all with p < .001). Seven to 10 variables were included in each model. There was high overlap in the variables included between the four models, and the sign of the correlation with voice quality was consistent for each variable across all four regression models. CONCLUSION: We found specific glottal geometry dynamics that correspond to voice quality in ADSD.

Head tremor in cervical dystonia: Quantifying severity with computer vision.

BACKGROUND: Head tremor (HT) is a common feature of cervical dystonia (CD), usually quantified by subjective observation. Technological developments offer alternatives for measuring HT severity that are objective and amenable to automation. OBJECTIVES: Our objectives were to develop CMOR (Computational Motor Objective Rater; a computer vision-based software system) to quantify oscillatory and directional aspects of HT from video recordings during a clinical examination and to test its convergent validity with clinical rating scales. METHODS: For 93 participants with isolated CD and HT enrolled by the Dystonia Coalition, we analyzed video recordings from an examination segment in which participants were instructed to let their head drift to its most comfortable dystonic position. We evaluated peak power, frequency, and directional dominance, and used Spearman's correlation to measure the agreement between CMOR and clinical ratings. RESULTS: Power averaged 0.90 (SD 1.80) deg2/Hz, and peak frequency 1.95 (SD 0.94) Hz. The dominant HT axis was pitch (antero/retrocollis) for 50%, roll (laterocollis) for 6%, and yaw (torticollis) for 44% of participants. One-sided t-tests showed substantial contributions from the secondary (t = 18.17, p < 0.0001) and tertiary (t = 12.89, p < 0.0001) HT axes. CMOR's HT severity measure positively correlated with the HT item on the Toronto Western Spasmodic Torticollis Rating Scale-2 (Spearman's rho = 0.54, p < 0.001). CONCLUSIONS: We demonstrate a new objective method to measure HT severity that requires only conventional video recordings, quantifies the complexities of HT in CD, and exhibits convergent validity with clinical severity ratings.

From null to midline: changes in head posture do not predictably change head tremor in cervical dystonia.

Introduction: A common view is that head tremor (HT) in cervical dystonia (CD) decreases when the head assumes an unopposed dystonic posture and increases when the head is held at midline. However, this has not been examined with objective measures in a large, multicenter cohort. Methods: For 80 participants with CD and HT, we analyzed videos from examination segments in which participants were instructed to 1) let their head drift to its most comfortable position (null point) and then 2) hold their head straight at midline. We used our previously developed Computational Motor Objective Rater (CMOR) to quantify changes in severity, amplitude, and frequency between the two postures. Results: Although up to 9% of participants had exacerbated HT in midline, across the whole cohort, paired t-tests reveal no significant changes in overall severity (t = -0.23, p = 0.81), amplitude (t = -0.80, p = 0.43), and frequency (t = 1.48, p = 0.14) between the two postures. Conclusions: When instructed to first let their head drift to its null point and then to hold their head straight at midline, most patient's changes in HT were below the thresholds one would expect from the sensitivity of clinical rating scales. Counter to common clinical impression, CMOR objectively showed that HT does not consistently increase at midline posture in comparison to the null posture.

Hold that pose: capturing cervical dystonia's head deviation severity from video.

OBJECTIVE: Deviated head posture is a defining characteristic of cervical dystonia (CD). Head posture severity is typically quantified with clinical rating scales such as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Because clinical rating scales are inherently subjective, they are susceptible to variability that reduces their sensitivity as outcome measures. The variability could be circumvented with methods to measure CD head posture objectively. However, previously used objective methods require specialized equipment and have been limited to studies with a small number of cases. The objective of this study was to evaluate a novel software system-the Computational Motor Objective Rater (CMOR)-to quantify multi-axis directionality and severity of head posture in CD using only conventional video camera recordings. METHODS: CMOR is based on computer vision and machine learning technology that captures 3D head angle from video. We used CMOR to quantify the axial patterns and severity of predominant head posture in a retrospective, cross-sectional study of 185 patients with isolated CD recruited from 10 sites in the Dystonia Coalition. RESULTS: The predominant head posture involved more than one axis in 80.5% of patients and all three axes in 44.4%. CMOR's metrics for head posture severity correlated with severity ratings from movement disorders neurologists using both the TWSTRS-2 and an adapted version of the Global Dystonia Rating Scale (rho = 0.59-0.68, all p <0.001). CONCLUSIONS: CMOR's convergent validity with clinical rating scales and reliance upon only conventional video recordings supports its future potential for large scale multisite clinical trials.

Choice modulates the neural dynamics of prediction error processing during rewarded learning.

Our ability to selectively engage with our environment enables us to guide our learning and to take advantage of its benefits. When facing multiple possible actions, our choices are a critical aspect of learning. In the case of learning from rewarding feedback, there has been substantial theoretical and empirical progress in elucidating the associated behavioral and neural processes, predominantly in terms of a reward prediction error, a measure of the discrepancy between actual versus expected reward. Nevertheless, the distinct influence of choice on prediction error processing and its neural dynamics remains relatively unexplored. In this study we used a novel paradigm to determine how choice influences prediction error processing and to examine whether there are correspondingly distinct neural dynamics. We recorded scalp electroencephalogram while healthy adults were administered a rewarded learning task in which choice trials were intermingled with control trials involving the same stimuli, motor responses, and probabilistic rewards. We used a temporal difference learning model of subjects' trial-by-trial choices to infer subjects' image valuations and corresponding prediction errors. As expected, choices were associated with lower overall prediction error magnitudes, most notably over the course of learning the stimulus-reward contingencies. Choices also induced a higher-amplitude relative positivity in the frontocentral event-related potential about 200 ms after reward signal onset that was negatively correlated with the differential effect of choice on the prediction error. Thus choice influences the neural dynamics associated with how reward signals are processed during learning. Behavioral, computational, and neurobiological models of rewarded learning should therefore accommodate a distinct influence for choice during rewarded learning.

The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia.

Head tremor and pain in cervical dystonia.

BACKGROUND: Although head tremor (HT) and pain are prevalent in cervical dystonia (CD), their joint relationship to phenotypic features of focal dystonia remains unclear. OBJECTIVES: We examined how severity of HT and pain are associated with age of CD onset and duration, and whether HT subtypes ("jerky" or "regular") exhibit distinct relationships between severity of HT and pain. METHODS: The severity of HT and pain were assessed with the Toronto Western Spasmodic Torticollis Rating Scale in retrospective review of 188 CD patients recruited through the Dystonia Coalition. RESULTS: HT severity was associated with longer CD duration (p < 0.0005), whereas pain severity was associated with younger age at onset (p = 0.043). HT severity and pain severity were not correlated for jerky HT (p = 0.996), but positively correlated for regular HT (p = 0.01). CONCLUSIONS: The distinct associations of HT and pain with age at onset, disease duration, and HT subtype further characterize the heterogeneity of CD's clinical presentation and suggest similarly heterogeneous underlying mechanisms.

Does Raising the Arms Modify Head Tremor Severity in Cervical Dystonia?

Background: A defining characteristic of dystonia is its position-dependence. In cervical dystonia (CD), sensory tricks ameliorate head tremor (HT). But it remains unknown whether raising the arms alone has the same impact. Methods: We analyzed data collected from patients enrolled by the Dystonia Coalition. For 120 patients with HT, we assessed how raising their arms without touching their head changed their HT severity. Results: Forty-eight out of 120 patients exhibited changes in HT severity when raising their arms. These patients were more likely to exhibit decreases in HT severity (N = 35) than increases (N = 13, χ2 (1, N = 48) = 10.1, p = 0.002). Demographic factors and sensory trick efficacy were not significant predictors of whether HT severity changed when raising their arms. Discussion: Raising the arms without touching the head is a posture that can reduce HT severity in some CD patients. Our results extend the concept of position-dependent motor symptoms in CD to include the position of the arms. Highlights: Head tremor (HT) is a prevalent symptom of cervical dystonia (CD) that can often be disabling. This study demonstrates that raising the arms without touching the head is a posture that can reduce HT severity in some CD patients. Our findings also identify a novel form of position-dependence in CD.

Ozone chemistry in western U.S. wildfire plumes.

Wildfires are a substantial but poorly quantified source of tropospheric ozone (O3). Here, to investigate the highly variable O3 chemistry in wildfire plumes, we exploit the in situ chemical characterization of western wildfires during the FIREX-AQ flight campaign and show that O3 production can be predicted as a function of experimentally constrained OH exposure, volatile organic compound (VOC) reactivity, and the fate of peroxy radicals. The O3 chemistry exhibits rapid transition in chemical regimes. Within a few daylight hours, the O3 formation substantially slows and is largely limited by the abundance of nitrogen oxides (NOx). This finding supports previous observations that O3 formation is enhanced when VOC-rich wildfire smoke mixes into NOx-rich urban plumes, thereby deteriorating urban air quality. Last, we relate O3 chemistry to the underlying fire characteristics, enabling a more accurate representation of wildfire chemistry in atmospheric models that are used to study air quality and predict climate.

Convergent evidence for abnormal striatal synaptic plasticity in dystonia.

Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor "use" may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes linking etiology to pathophysiology of the disease.

Surgical aspects and biological considerations of arteriovenous fistula placement.

Since the Fistula First Initiative was formulated in 2003, providers and payers have increasingly emphasized the need to create more arteriovenous fistulae. To maximize the chances of successful fistula maturation, a thorough understanding of the biology and surgical aspects of fistula placement are essential. A functional endothelium in the target vessels is the prerequisite for the adaptive remodeling of the vessel wall, which has to take place after fistula formation. Mechanoreceptors of the endothelium sense the increase in shear stress and, through a variety of activated signaling cascades, induce the necessary changes and vasodilation of the respective vessels. The successful fistula placement starts with a thorough preoperative evaluation, which focuses on protecting the target vessels and avoiding intravenous catheters and devices. Intraoperatively, the risk of endothelial dysfunction and hyperplasia is further minimized through an atraumatic dissection with minimal manipulation of the vein and artery. The surgical technique should also focus on decreasing the vessel compliance mismatch and avoiding an inflammatory response secondary to hematoma formation. Postoperatively, the fistula must be diligently monitored for the complications of thrombosis, postoperative steal syndrome, neuropathy, aneurysm formation, infection, and high-output cardiac failure. Early recognition of a problem is the key to saving an otherwise doomed fistula. An armamentarium of percutaneous techniques is available to the access surgeon to treat the most common causes of failed access formation. However, in some cases a surgical revision of the access site through patch angioplasty, a jump graft, and graft interposition is necessary to create a fistula which can be successfully used for hemodialysis.

Basal ganglia and cerebellar circuits have distinct roles in blepharospasm.

INTRODUCTION: To identify areas of brain activity associated with involuntary muscle contractions in patients with blepharospasm using functional MRI. METHODS: 15 patients with blepharospasm underwent 8-min resting state scans with spontaneous orbicularis oculi muscle contractions simultaneously recorded using MRI-compatible surface electromyography. Spasm severity and spasm onset/offset were modeled using the amplitude of the electromyography signal (EMG-Amp) and its first temporal derivative (EMG-Onset), respectively, and included in a multiple regression functional MRI analysis using SPM12. Primary outcome was within-group blood-oxygen-level dependent activations that co-varied with EMG-Amp and EMG-Onset following correction for multiple comparisons for an overall cluster corrected p < 0.05. Secondary analyses included testing for correlations between imaging findings and symptom severity, as measured by clinical dystonia rating scales, using an uncorrected voxel-level threshold of p < 0.001. RESULTS: Imaging data from one subject were excluded due to excessive movement. EMG-Amp co-activated within the left sensorimotor cortex and cerebellum, as well as right lingual gyrus and superior temporal gyrus. EMG-Onset co-activated within the left posterior putamen/pallidum and a frontal eye field region in the left superior frontal gyrus. Symptom severity and EMG-Amp significantly co-varied in a small cluster within the left cerebellum. CONCLUSION: Our preliminary findings here suggest that cerebello-cortical circuits in blepharospasm could drive the intensity of eyelid spasms while basal ganglia circuits are associated with the triggering of spasms. This supports the network model for dystonia and identifies specific areas of involvement consistent with known brain regions responsible for control of movement.

Postural Directionality and Head Tremor in Cervical Dystonia.

Background: Although abnormal head and neck postures are defining features of cervical dystonia (CD), head tremor (HT) is also common. However, little is known about the relationship between abnormal postures and HT in CD. Methods: We analyzed clinical data and video recordings from 185 patients enrolled by the Dystonia Coalition. We calculated the likelihood of their HT and HT type ("regular" vs. "jerky") given directionality of abnormal head postures, disease duration, sex, and age. Results: Patients with retrocollis were more likely to have HT than patients with anterocollis (X2 (1, N = 121) = 7.98, p = 0.005). There was no difference in HT likelihood given left or right turning in laterocollis and rotation. Patients with HT had longer disease duration (t(183) = 2.27, p = 0.024). There was no difference in age between patients with and without HT. In a logistic regression model, anterocollis/retrocollis direction (X2 (1, N = 121) = 6.04, p = 0.014), disease duration (X2 (1, N = 121) = 7.28, p = 0.007), and the interaction term between age and disease duration (X2 (1, N = 121) = 7.77, p = 0.005) collectively contributed to HT likelihood. None of the postural directionality or demographic variables were associated with differential likelihood of having regular versus jerky HT. Discussion: We found that HT is more likely for CD patients with a specific directionality in their predominant posture. Our finding that CD patients with longer disease duration have a higher likelihood of HT also raises the question of whether HT becomes more likely over time in individual patients.

It's tricky: Rating alleviating maneuvers in cervical dystonia.

OBJECTIVES: To investigate hypothesized sources of error when quantifying the effect of the sensory trick in cervical dystonia (CD) with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-2), test strategies to mitigate them, and provide guidance for future research on the sensory trick. METHODS: Previous analyses suggested the sensory trick (or "alleviating maneuver", AM) item be removed from the TWSTRS-2 because of its poor clinimetric properties. We hypothesized three sources of clinimetric weakness for rating the AM: 1) whether patients were given sufficient time to demonstrate their AM; 2) whether patients' CD was sufficiently severe for detecting AM efficacy; and 3) whether raters were inadvertently rating the item in reverse of scale instructions. We tested these hypotheses with video recordings and TWSTRS-2 ratings by one "site rater" and a panel of five "video raters" for each of 185 Dystonia Coalition patients with isolated CD. RESULTS: Of 185 patients, 23 (12%) were not permitted sufficient testing time to exhibit an AM, 23 (12%) had baseline CD too mild to allow confident rating of AM effect, and 1 site- and 1 video-rater each rated the AM item with a reverse scoring convention. When these confounds were eliminated in step-wise fashion, the item's clinimetric properties improved. CONCLUSIONS: The AM's efficacy can contribute to measuring CD motor severity by addressing identified sources of error during its assessment and rating. Given the AM's sensitive diagnostic and potential pathophysiologic significance, we also provide guidance on modifications to how AMs can be assessed in future CD research.

Investigation of factors controlling PM2.5 variability across the South Korean Peninsula during KORUS-AQ.

The Korea - United States Air Quality Study (May - June 2016) deployed instrumented aircraft and ground-based measurements to elucidate causes of poor air quality related to high ozone and aerosol concentrations in South Korea. This work synthesizes data pertaining to aerosols (specifically, particulate matter with aerodynamic diameters <2.5 micrometers, PM2.5) and conditions leading to violations of South Korean air quality standards (24-hr mean PM2.5 < 35 µg m-3). PM2.5 variability from AirKorea monitors across South Korea is evaluated. Detailed data from the Seoul vicinity are used to interpret factors that contribute to elevated PM2.5. The interplay between meteorology and surface aerosols, contrasting synoptic-scale behavior vs. local influences, is presented. Transboundary transport from upwind sources, vertical mixing and containment of aerosols, and local production of secondary aerosols are discussed. Two meteorological periods are probed for drivers of elevated PM2.5. Clear, dry conditions, with limited transport (Stagnant period), promoted photochemical production of secondary organic aerosol from locally emitted precursors. Cloudy humid conditions fostered rapid heterogeneous secondary inorganic aerosol production from local and transported emissions (Transport/Haze period), likely driven by a positive feedback mechanism where water uptake by aerosols increased gas-to-particle partitioning that increased water uptake. Further, clouds reduced solar insolation, suppressing mixing, exacerbating PM2.5 accumulation in a shallow boundary layer. The combination of factors contributing to enhanced PM2.5 is challenging to model, complicating quantification of contributions to PM2.5 from local versus upwind precursors and production. We recommend co-locating additional continuous measurements at a few AirKorea sites across South Korea to help resolve this and other outstanding questions: carbon monoxide/carbon dioxide (transboundary transport tracer), boundary layer height (surface PM2.5 mixing depth), and aerosol composition with aerosol liquid water (meteorologically-dependent secondary production). These data would aid future research to refine emissions targets to further improve South Korean PM2.5 air quality.