Increasing Efficiency With Point-of-Care Ultrasound-Guided Arthrocentesis: A Case Report and Procedure Demonstration.

Patients with chief complaints of musculoskeletal pain comprise a significant portion of emergency department (ED) visits. Identifying and utilizing methods to expedite diagnosis in these cases may help reduce ED crowding, improve outcomes, and increase patient satisfaction. We present a case in which a 52-year-old man presented to the ED with complaints of unilateral right knee pain, swelling, and stiffness. An initial plain film X-ray showed a large suprapatellar effusion over the patient's arthritic right knee. Point-of-care ultrasound (POCUS) was used by an ED physician to facilitate a suprapatellar arthrocentesis. The patient tolerated the procedure well, remarking that he had no pain during or after its completion. POCUS can increase the accuracy, efficacy, and speed of procedures for which physicians have traditionally used landmarks or formal radiology consultations. While POCUS can prove helpful, barriers to its widespread implementation still remain. However, these barriers can be addressed with relative ease.

Elevated Mood Induced by Subthalamic Nucleus Deep Brain Stimulation: A Video-Recorded Case Report.

Background: Deep brain stimulation (DBS) can be an effective therapy to control motor signs in patients with Parkinson's disease (PD). However, subthalamic nucleus (STN) DBS can induce undesirable psychiatric adverse effects, including elevated mood. Case report: We reported a video case of a 73-year-old male implanted with bilateral STN DBS who experienced stimulation-induced elevated mood. A correlation between mood changes and enhanced activation of the ventromedial region in the left STN was observed. Discussion: This video case report illustrates STN DBS-induced elevated mood and enhances early symptom recognition for patients and diagnostic awareness for professionals.

Responsive Versus Continuous Deep Brain Stimulation for Speech in Essential Tremor: A Pilot Study.

BACKGROUND: Responsive deep brain stimulation (rDBS) uses physiological signals to deliver stimulation when needed. rDBS is hypothesized to reduce stimulation-induced speech effects associated with continuous DBS (cDBS) in patients with essential tremor (ET). OBJECTIVE: To determine if rDBS reduces cDBS speech-related side effects while maintaining tremor suppression. METHODS: Eight ET participants with thalamic DBS underwent unilateral rDBS. Both speech evaluations and tremor severity were assessed across three conditions (DBS OFF, cDBS ON, and rDBS ON). Speech was analyzed using intelligibility ratings. Tremor severity was scored using the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: During unilateral cDBS, participants experienced reduced speech intelligibility (P = 0.025) compared to DBS OFF. rDBS was not associated with a deterioration of intelligibility. Both rDBS (P = 0.026) and cDBS (P = 0.038) improved the contralateral TRS score compared to DBS OFF. CONCLUSIONS: rDBS maintained speech intelligibility without loss of tremor suppression. A larger prospective chronic study of rDBS in ET is justified. © 2024 International Parkinson and Movement Disorder Society.

Chronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson's disease.

Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson's disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.

Local Food System Approaches to Address Food and Nutrition Security among Low-Income Populations: A Systematic Review.

Food and nutrition insecurity disproportionately impact low-income households in the United States, contributing to higher rates of chronic diseases among this population. Addressing this challenge is complex because of various factors affecting the availability and accessibility of nutritious food. Short value chain (SVC) models, informally known as local food systems, offer a systemic approach that aims to optimize resources and align values throughout and beyond the food supply chain. Although specific SVC interventions, such as farmers markets, have been studied individually, a comprehensive review of SVC models was pursued to evaluate their relative impact on food security, fruit and vegetable intake, diet quality, health-related markers, and barriers and facilitators to participation among low-income households. Our systematic literature search identified 37 articles representing 34 studies from 2000-2020. Quantitative, qualitative, and mixed-method studies revealed that farmers market interventions had been evaluated more extensively than other SVC models (i.e., produce prescription programs, community-supported agriculture, mobile markets, food hubs, farm stands, and farm-to-school). Fruit and vegetable intake was the most measured outcome; other outcomes were less explored or not measured at all. Qualitative insights highlighted common barriers to SVC use, such as lack of program awareness, limited accessibility, and cultural incongruence, whereas facilitators included health-promoting environments, community cohesion, financial incentives, and high-quality produce. Social marketing and dynamic nutrition education appeared to yield positive program outcomes. Financial incentives were used in many studies, warranting further investigation into optimal amounts across varying environmental contexts. SVC models are increasingly germane to national goals across the agriculture, social, and health care sectors. This review advances the understanding of key knowledge gaps related to their implementation and impact; it emphasizes the need for research to analyze SVC potential comprehensively across the rural-urban continuum and among diverse communities through long-term studies of measurable health impact and mixed-method studies investigating implementation best practices. This trial was registered at PROSPERO as CRD42020206532.

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Deep brain stimulation for refractory major depressive disorder: a comprehensive review.

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms.

Leveraging social networks for identification of people with HIV who are virally unsuppressed.

OBJECTIVES: This study investigates primary peer-referral engagement (PRE) strategies to assess which strategy results in engaging higher numbers of people with HIV (PWH) who are virally unsuppressed. DESIGN: We develop a modeling study that simulates an HIV epidemic (transmission, disease progression, and viral evolution) over 6 years using an agent-based model followed by simulating PRE strategies. We investigate two PRE strategies where referrals are based on social network strategies (SNS) or sexual partner contact tracing (SPCT). METHODS: We parameterize, calibrate, and validate our study using data from Chicago on Black sexual minority men to assess these strategies for a population with high incidence and prevalence of HIV. For each strategy, we calculate the number of PWH recruited who are undiagnosed or out-of-care (OoC) and the number of direct or indirect transmissions. RESULTS: SNS and SPCT identified 256.5 [95% confidence interval (CI) 234-279] and 15 (95% CI 7-27) PWH, respectively. Of these, SNS identified 159 (95% CI 142-177) PWH OoC and 32 (95% CI 21-43) PWH undiagnosed compared with 9 (95% CI 3-18) and 2 (95% CI 0-5) for SPCT. SNS identified 15.5 (95% CI 6-25) and 7.5 (95% CI 2-11) indirect and direct transmission pairs, whereas SPCT identified 6 (95% CI 0-8) and 5 (95% CI 0-8), respectively. CONCLUSION: With no testing constraints, SNS is the more effective strategy to identify undiagnosed and OoC PWH. Neither strategy is successful at identifying sufficient indirect or direct transmission pairs to investigate transmission networks.

Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases.

PURPOSE: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vß) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vß would eliminate the malignant clone while having minimal effects on healthy T cells. EXPERIMENTAL DESIGN: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vß13.3. We developed a panel of anti-Vß13.3 antibodies to test for binding and elimination of the malignant T-cell clone. RESULTS: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vß13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vß13.3 were also killed by antibody administration in an in vivo murine model. CONCLUSIONS: This approach serves as an outline for development of therapeutics that can treat clonal T-cell-based malignancies and potentially other T-cell-mediated diseases. See related commentary by Varma and Diefenbach, p. 4024.

Robustness and reproducibility of simple and complex synthetic logic circuit designs using a DBTL loop.

Computational tools addressing various components of design-build-test-learn (DBTL) loops for the construction of synthetic genetic networks exist but do not generally cover the entire DBTL loop. This manuscript introduces an end-to-end sequence of tools that together form a DBTL loop called Design Assemble Round Trip (DART). DART provides rational selection and refinement of genetic parts to construct and test a circuit. Computational support for experimental process, metadata management, standardized data collection and reproducible data analysis is provided via the previously published Round Trip (RT) test-learn loop. The primary focus of this work is on the Design Assemble (DA) part of the tool chain, which improves on previous techniques by screening up to thousands of network topologies for robust performance using a novel robustness score derived from dynamical behavior based on circuit topology only. In addition, novel experimental support software is introduced for the assembly of genetic circuits. A complete design-through-analysis sequence is presented using several OR and NOR circuit designs, with and without structural redundancy, that are implemented in budding yeast. The execution of DART tested the predictions of the design tools, specifically with regard to robust and reproducible performance under different experimental conditions. The data analysis depended on a novel application of machine learning techniques to segment bimodal flow cytometry distributions. Evidence is presented that, in some cases, a more complex build may impart more robustness and reproducibility across experimental conditions. Graphical Abstract.

Brain Recording Analysis and Visualization Online (BRAVO): An open-source visualization tool for deep brain stimulation data.

BACKGROUND: Deep brain stimulation (DBS) devices with neural recording capabilities are commercially available and may potentially improve clinical care and advance research. However, tools, to visualize neural recording data have been limited. These tools in general, require custom-made software for processing and analysis. The development of new tools will be critical for clinicians and researchers to fully leverage the latest device capabilities. OBJECTIVE: There is an urgent need for a user-friendly tool for in-depth visualization and analysis of brain signals and of DBS data. METHODS AND RESULTS: The Brain Recording Analysis and Visualization Online (BRAVO) platform was developed to easily import, visualize, and analyze brain signals. This Python-based web interface has been designed and implemented on a Linux server. The tool processes the session files from DBS programming generated by a clinical 'programming' tablet. The platform is capable of parsing and organizing neural recordings for longitudinal analysis. We present the platform and cases exemplifying its application and use. CONCLUSION: The BRAVO platform is an accessible easy-to-use, open-source web interface for clinicians and researchers to apply for analysis of longitudinal neural recording data. The tool can be used for both clinical and research applications.

Globus pallidus internus deep brain stimulation evokes resonant neural activity in Parkinson's disease.

Globus pallidus internus deep brain stimulation is an established therapy for patients with medication-refractory Parkinson's disease. Clinical outcomes are highly dependent on applying stimulation to precise locations in the brain. However, robust neurophysiological markers are needed to determine the optimal electrode location and to guide postoperative stimulation parameter selection. In this study, we evaluated evoked resonant neural activity in the pallidum as a potential intraoperative marker to optimize targeting and stimulation parameter selection to improve outcomes of deep brain stimulation for Parkinson's disease. Intraoperative local field potential recordings were acquired in 22 patients with Parkinson's disease undergoing globus pallidus internus deep brain stimulation implantation (N = 27 hemispheres). A control group of patients undergoing implantation in the subthalamic nucleus (N = 4 hemispheres) for Parkinson's disease or the thalamus for essential tremor (N = 9 patients) were included for comparison. High-frequency (135 Hz) stimulation was delivered from each electrode contact sequentially while recording the evoked response from the other contacts. Low-frequency stimulation (10 Hz) was also applied as a comparison. Evoked resonant neural activity features, including amplitude, frequency and localization were measured and analysed for correlation with empirically derived postoperative therapeutic stimulation parameters. Pallidal evoked resonant neural activity elicited by stimulation in the globus pallidus internus or externus was detected in 26 of 27 hemispheres and varied across hemispheres and across stimulating contacts within individual hemispheres. Bursts of high-frequency stimulation elicited evoked resonant neural activity with similar amplitudes (P = 0.9) but a higher frequency (P = 0.009) and a higher number of peaks (P = 0.004) than low-frequency stimulation. We identified a 'hotspot' in the postero-dorsal pallidum where stimulation elicited higher evoked resonant neural activity amplitudes (P < 0.001). In 69.6% of hemispheres, the contact that elicited the maximum amplitude intraoperatively matched the contact empirically selected for chronic therapeutic stimulation by an expert clinician after 4 months of programming sessions. Pallidal and subthalamic nucleus evoked resonant neural activity were similar except for lower pallidal amplitudes. No evoked resonant neural activity was detected in the essential tremor control group. Given its spatial topography and correlation with postoperative stimulation parameters empirically selected by expert clinicians, pallidal evoked resonant neural activity shows promise as a potential marker to guide intraoperative targeting and to assist the clinician with postoperative stimulation programming. Importantly, evoked resonant neural activity may also have the potential to guide directional and closed-loop deep brain stimulation programming for Parkinson's disease.

Tourette syndrome: clinical features, pathophysiology, and treatment.

Tourette syndrome is a chronic neurodevelopmental disorder characterised by motor and phonic tics that can substantially diminish the quality of life of affected individuals. Evaluating and treating Tourette syndrome is complex, in part due to the heterogeneity of symptoms and comorbidities between individuals. The underlying pathophysiology of Tourette syndrome is not fully understood, but recent research in the past 5 years has brought new insights into the genetic variations and the alterations in neurophysiology and brain networks contributing to its pathogenesis. Treatment options for Tourette syndrome are expanding with novel pharmacological therapies and increased use of deep brain stimulation for patients with symptoms that are refractory to pharmacological or behavioural treatments. Potential predictors of patient responses to therapies for Tourette syndrome, such as specific networks modulated during deep brain stimulation, can guide clinical decisions. Multicentre data sharing initiatives have enabled several advances in our understanding of the genetics and pathophysiology of Tourette syndrome and will be crucial for future large-scale research and in refining effective treatments.

Integrative analysis of drug response and clinical outcome in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.

Calibration of an Adaptive Genetic Algorithm for Modeling Opinion Diffusion.

Genetic algorithms mimic the process of natural selection in order to solve optimization problems with minimal assumptions and perform well when the objective function has local optima on the search space. These algorithms treat potential solutions to the optimization problem as chromosomes, consisting of genes which undergo biologically-inspired operators to identify a better solution. Hyperparameters or control parameters determine the way these operators are implemented. We created a genetic algorithm in order to fit a DeGroot opinion diffusion model using limited data, making use of selection, blending, crossover, mutation, and survival operators. We adapted the algorithm from a genetic algorithm for design of mixture experiments, but the new algorithm required substantial changes due to model assumptions and the large parameter space relative to the design space. In addition to introducing new hyperparameters, these changes mean the hyperparameter values suggested for the original algorithm cannot be expected to result in optimal performance. To make the algorithm for modeling opinion diffusion more accessible to researchers, we conduct a simulation study investigating hyperparameter values. We find the algorithm is robust to the values selected for most hyperparameters and provide suggestions for initial, if not default, values and recommendations for adjustments based on algorithm output.

Patient-specific structural connectivity informs outcomes of responsive neurostimulation for temporal lobe epilepsy.

OBJECTIVE: Responsive neurostimulation is an effective therapy for patients with refractory mesial temporal lobe epilepsy. However, clinical outcomes are variable, few patients become seizure-free, and the optimal stimulation location is currently undefined. The aim of this study was to quantify responsive neurostimulation in the mesial temporal lobe, identify stimulation-dependent networks associated with seizure reduction, and determine if stimulation location or stimulation-dependent networks inform outcomes. METHODS: We modeled patient-specific volumes of tissue activated and created probabilistic stimulation maps of local regions of stimulation across a retrospective cohort of 22 patients with mesial temporal lobe epilepsy. We then mapped the network stimulation effects by seeding tractography from the volume of tissue activated with both patient-specific and normative diffusion-weighted imaging. We identified networks associated with seizure reduction across patients using the patient-specific tractography maps and then predicted seizure reduction across the cohort. RESULTS: Patient-specific stimulation-dependent connectivity was correlated with responsive neurostimulation effectiveness after cross-validation (p = .03); however, normative connectivity derived from healthy subjects was not (p = .44). Increased connectivity from the volume of tissue activated to the medial prefrontal cortex, cingulate cortex, and precuneus was associated with greater seizure reduction. SIGNIFICANCE: Overall, our results suggest that the therapeutic effect of responsive neurostimulation may be mediated by specific networks connected to the volume of tissue activated. In addition, patient-specific tractography was required to identify structural networks correlated with outcomes. It is therefore likely that altered connectivity in patients with epilepsy may be associated with the therapeutic effect and that utilizing patient-specific imaging could be important for future studies. The structural networks identified here may be utilized to target stimulation in the mesial temporal lobe and to improve seizure reduction for patients treated with responsive neurostimulation.

Past, Present, and Future of Deep Brain Stimulation: Hardware, Software, Imaging, Physiology and Novel Approaches.

Deep brain stimulation (DBS) has advanced treatment options for a variety of neurologic and neuropsychiatric conditions. As the technology for DBS continues to progress, treatment efficacy will continue to improve and disease indications will expand. Hardware advances such as longer-lasting batteries will reduce the frequency of battery replacement and segmented leads will facilitate improvements in the effectiveness of stimulation and have the potential to minimize stimulation side effects. Targeting advances such as specialized imaging sequences and "connectomics" will facilitate improved accuracy for lead positioning and trajectory planning. Software advances such as closed-loop stimulation and remote programming will enable DBS to be a more personalized and accessible technology. The future of DBS continues to be promising and holds the potential to further improve quality of life. In this review we will address the past, present and future of DBS.