Comprehensive Lipidomic Automation Workflow using Large Language Models.

Lipidomics generates large data that makes manual annotation and interpretation challenging. Lipid chemical and structural diversity with structural isomers further complicates annotation. Although, several commercial and open-source software for targeted lipid identification exists, it lacks automated method generation workflows and integration with statistical and bioinformatics tools. We have developed the Comprehensive Lipidomic Automated Workflow (CLAW) platform with integrated workflow for parsing, detailed statistical analysis and lipid annotations based on custom multiple reaction monitoring (MRM) precursor and product ion pair transitions. CLAW contains several modules including identification of carbon-carbon double bond position(s) in unsaturated lipids when combined with ozone electrospray ionization (OzESI)-MRM methodology. To demonstrate the utility of the automated workflow in CLAW, large-scale lipidomics data was collected with traditional and OzESI-MRM profiling on biological and non-biological samples. Specifically, a total of 1497 transitions organized into 10 MRM-based mass spectrometry methods were used to profile lipid droplets isolated from different brain regions of 18-24 month-old Alzheimer's disease mice and age-matched wild-type controls. Additionally, triacyclglycerols (TGs) profiles with carbon-carbon double bond specificity were generated from canola oil samples using OzESI-MRM profiling. We also developed an integrated language user interface with large language models using artificially intelligent (AI) agents that permits users to interact with the CLAW platform using a chatbot terminal to perform statistical and bioinformatic analyses. We envision CLAW pipeline to be used in high-throughput lipid structural identification tasks aiding users to generate automated lipidomics workflows ranging from data acquisition to AI agent-based bioinformatic analysis.

Continuous flow synthesis of pyridinium salts accelerated by multi-objective Bayesian optimization with active learning.

We report a human-in-the-loop implementation of the multi-objective experimental design via a Bayesian optimization platform (EDBO+) towards the optimization of butylpyridinium bromide synthesis under continuous flow conditions. The algorithm simultaneously optimized reaction yield and production rate (or space-time yield) and generated a well defined Pareto front. The versatility of EDBO+ was demonstrated by expanding the reaction space mid-campaign by increasing the upper temperature limit. Incorporation of continuous flow techniques enabled improved control over reaction parameters compared to common batch chemistry processes, while providing a route towards future automated syntheses and improved scalability. To that end, we applied the open-source Python module, nmrglue, for semi-automated nuclear magnetic resonance (NMR) spectroscopy analysis, and compared the acquired outputs against those obtained through manual processing methods from spectra collected on both low-field (60 MHz) and high-field (400 MHz) NMR spectrometers. The EDBO+ based model was retrained with these four different datasets and the resulting Pareto front predictions provided insight into the effect of data analysis on model predictions. Finally, quaternization of poly(4-vinylpyridine) with bromobutane illustrated the extension of continuous flow chemistry to synthesize functional materials.

Telehealth for Assessing and Managing Tardive Dyskinesia: Expert Insights from a Cross-Disciplinary Virtual Treatment Panel.

Introduction: Publications on the integration of telehealth in the care of patients with movement disorders are increasing, but little has been presented regarding its use in tardive dyskinesia (TD), a drug-induced movement disorder associated with prolonged exposure to dopamine receptor blocking agents. This study was conducted to address that knowledge gap, based on insights from a panel of TD experts. Methods: In 2020, six neurologists, three psychiatrists, and three psychiatric nurse practitioners participated in individual semistructured interviews about in-person and virtual TD assessment and management in their practices. Two virtual roundtables were then conducted to consolidate findings from these interviews. Results: The panel agreed that despite the challenges of virtual TD assessment (e.g., technology issues, difficulty observing entire body, inability to conduct thorough neurological examinations), telehealth can offer benefits (e.g., fewer missed appointments, reduced time/cost, easier access to family/caregiver feedback). The panel also agreed that telehealth should be combined with periodic in-person visits, and they recommended an in-person TD assessment within 6 months before the first virtual visit and at least one in-person assessment every 6 months thereafter. Additional best practices for TD telehealth included implementing video, involving family/caregivers, and providing preappointment instructions to help patients prepare their technology and environment. Conclusions: Telehealth is not a substitute for in-person visits but can be a helpful complement to in-person clinical care. Clinicians can optimize virtual visits in patients at risk of TD by using targeted questions to identify TD and evaluate its impact and by providing education about approved TD treatments.

Identification of Monomethyl Branched-Chain Lipids by a Combination of Liquid Chromatography Tandem Mass Spectrometry and Charge-Switching Chemistries.

While various mass spectrometric approaches have been applied to lipid analysis, unraveling the extensive structural diversity of lipids remains a significant challenge. Notably, these approaches often fail to differentiate between isomeric lipids─a challenge that is particularly acute for branched-chain fatty acids (FAs) that often share similar (or identical) mass spectra to their straight-chain isomers. Here, we utilize charge-switching strategies that combine ligated magnesium dications with deprotonated fatty acid anions. Subsequent activation of these charge inverted anions yields mass spectra that differentiate anteiso-branched- from straight-chain and iso-branched-chain FA isomers with the predictable fragmentation enabling de novo assignment of anteiso branch points. The application of these charge-inversion chemistries in both gas- and solution-phase modalities is demonstrated to assign the position of anteiso-methyl branch-points in FAs and, with the aid of liquid chromatography, can be extended to de novo assignment of additional branching sites via predictable fragmentation patterns as methyl branching site(s) move closer to the carboxyl carbon. The gas-phase approach is shown to be compatible with top-down structure elucidation of complex lipids such as phosphatidylcholines, while the integration of solution-phase charge-inversion with reversed phase liquid chromatography enables separation and unambiguous identification of FA structures within isomeric mixtures. Taken together, the presented charge-switching MS-based technique, in combination with liquid chromatography, enables the structural identification of branched-chain FA without the requirement of authentic methyl-branched FA reference standards.

Exercise-induced neuroplasticity in human Parkinson's disease: What is the evidence telling us?

INTRODUCTION: While animal models of exercise and PD have pushed the field forward, few studies have addressed exercise-induced neuroplasticity in human PD. METHOD: As a first step toward promoting greater international collaboration on exercise-induced neuroplasticity in human PD, we present data on 8 human PD studies (published between 2008 and 2015) with 144 adults with PD of varying disease severity (Hoehn and Yahr stage 1 to stage 3), using various experimental (e.g., randomized controlled trial) and quasi-experimental designs on the effects of cognitive and physical activity on brain structure or function in PD. We focus on plasticity mechanisms of intervention-induced increases in maximal corticomotor excitability, exercise-induced changes in voxel-based gray matter volume changes and increases in exercise-induced serum levels of brain derived neurotrophic factor (BDNF). Finally, we provide a future perspective for promoting international, collaborative research on exercise-induced neuroplasticity in human PD. CONCLUSION: An emerging body of evidence suggests exercise triggers several plasticity related events in the human PD brain including corticomotor excitation, increases and decreases in gray matter volume and changes in BDNF levels.

Parkinson patients as partners in care.

Increasing physical activity, as part of an active lifestyle, is an important health goal for individuals with Parkinson's disease (PD). Exercise can positively impact health related quality of life. Given this, how can we promote physically active lifestyles among PD patients (most of whom are sedentary)? Here we suggest that health care professionals could significantly expand their impact by collaborating with PD patients and their spouses (or caregivers) as partners-in-care. We outline reasons why partners-in-care approaches are important in PD, including the need to increase social capital, which deals with issues of trust and the value of social networks in linking members of a community. We then present results of a qualitative study involving partners-in-care exercise beliefs among 19 PD patients and spouses, and conclude with our perspective on future benefits of this approach.

Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson's disease.

It has been previously well established that the use of dopaminergic agents in Parkinson's disease may contribute to behavioral disturbances such as dopamine dysregulation syndrome (DDS), impulse control disorders (ICD), and punding. ICD and punding have been most commonly addressed by reducing dose or by discontinuing the use of a dopamine agonist. Treatment of DDS has proven more challenging, and to date there has been no standard approach. In this paper, we review a series of four patients who met criteria for DDS, who were all refractory to medication adjustments. The DDS symptoms responded by the addition of valproic acid in all cases.

Unilateral GPi-DBS as a treatment for levodopa-induced respiratory dyskinesia in Parkinson disease.

BACKGROUND: Respiratory dyskinesia is a rare but disabling complication of levodopa therapy for Parkinson disease; however, its treatment has been limited to medication optimization. CASE REPORT: A 72-year-old woman with a 6-year history of Parkinson disease presented with severe and debilitating levodopa-induced respiratory dyskinesia, which manifested with a short and shallow breathing pattern and panting. These symptoms were observed coincident with limb and truncal dyskinesias. Both respiratory and limb/trunk dyskinesias were addressed by the implantation of a unilateral globus pallidus interna deep brain stimulator (GPi-DBS). CONCLUSIONS: Although the mechanism of involvement of the respiratory system in dyskinesia is unknown, GPi-DBS seems to be a potentially viable treatment option for these patients.

Promoting exercise in Parkinson's disease through community-based participatory research.

Parkinson's disease (PD) is a chronic, progressive, as-of-yet incurable, neurodegenerative condition affecting the nigro-striatal dopaminergic system. Emerging evidence suggests the importance of exercise in improving the trajectory of PD. Yet few people with PD are physically active. One challenge that healthcare professionals face in the 21st century is how to deliver physical activity programs to the population of individuals living with PD. A novel approach to delivering physical activity to people with PD is introduced - termed community-based participatory research (CBPR) - which engages people with PD and patient advocates as co-researchers in the development and implementation of community-based exercise programs. The authors describe the CBPR approach and provide several recent examples of community exercise programs that are steps in the direction of developing the CBPR model. This is followed by a discussion of what a more fully realized CBPR model might look like. Finally, the authors describe some obstacles to conducting CBPR and suggest strategies for overcoming them. It is argued that people with PD are an integral component of delivering the exercise intervention.

The effect of emergency department crowding on patient satisfaction for admitted patients.

OBJECTIVES: The objective was to study the association between factors related to emergency department (ED) crowding and patient satisfaction. METHODS: The authors performed a retrospective cohort study of all patients admitted through the ED who completed Press-Ganey patient satisfaction surveys over a 2-year period at a single academic center. Ordinal and binary logistic regression was used to study the association between validated ED crowding factors (such as hallway placement, waiting times, and boarding times) and patient satisfaction with both ED care and assessment of satisfaction with the overall hospitalization. RESULTS: A total of 1,501 hospitalizations for 1,469 patients were studied. ED hallway use was broadly predictive of a lower likelihood of recommending the ED to others, lower overall ED satisfaction, and lower overall satisfaction with the hospitalization (p < 0.05). Prolonged ED boarding times and prolonged treatment times were also predictive of lower ED satisfaction and lower satisfaction with the overall hospitalization (p < 0.05). Measures of ED crowding and ED waiting times predicted ED satisfaction (p < 0.05), but were not predictive of satisfaction with the overall hospitalization. CONCLUSIONS: A poor ED service experience as measured by ED hallway use and prolonged boarding time after admission are adversely associated with ED satisfaction and predict lower satisfaction with the entire hospitalization. Efforts to decrease ED boarding and crowding might improve patient satisfaction.

Throat clicking as the initial symptom of Parkinson's disease.

The presenting manifestations of Parkinson's disease (PD) are variable, but a majority of patients note tremor as the initial symptom. Others complain of slowing of movements, loss of dexterity, fatigue, or changes in handwriting as initial symptoms. We describe a patient who developed an unusual clicking sound emanating from his throat as the initial manifestation of PD.