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Poly-D,L-lactic acid (PDLLA) microspheres, marketed globally as Aesthefill® (Regen Biotech, Seoul, South Korea), are recognized for their biocompatible and biostimulatory properties, positioning them as a preferred option in aesthetic medicine. This article presents consensus recommendations from Brazilian experts on the reconstitution and clinical application of PDLLA for facial and non-facial treatments. Developed using a modified Delphi method with contributions from leading dermatologists and plastic surgeons, the consensus outlines protocols for reconstitution, injection techniques, and patient management. Key recommendations include reconstitution with 7– 8 mL of sterile water for injection, the addition of lidocaine to improve patient comfort, and a preference for targeting the superficial subcutaneous layer. Dosing guidelines are specifically tailored to each treatment area and the desired degree of correction, underscoring the importance of personalized treatment plans. Maintenance treatments are advised at biennial intervals or at shorter intervals for patients exhibiting accelerated collagen degradation. The consensus also highlights the need for proper training and patient screening to minimize adverse effects, such as nodules and granulomas. This comprehensive guide aims to standardize the use of PDLLA, prioritizing patient safety and optimizing outcomes. While clinical trials evaluating PDLLA's aesthetic indications remain limited, these evidence-based guidelines bridge the gap by offering practical protocols grounded in clinical expertise. Further research is encouraged to validate these recommendations and explore new applications for PDLLA in aesthetic medicine. Plain Language Summary: Poly-D, L-lactic acid (PDLLA) microspheres are small particles used in aesthetic medicine to improve skin appearance by stimulating collagen production. This summary outlines expert recommendations from experts on preparing and using PDLLA for facial and body treatments. Why was the study done? The study aimed to create standardized guidelines to help practitioners achieve the best results and ensure patient safety when using PDLLA for cosmetic purposes. What did the researchers do and find? They used a method called the Delphi approach to gather and refine recommendations on the reconstitution and injection of PDLLA. By consensus, the experts who participated in this study recommend using of sterile water for injection to prepare the PDLLA and adding lidocaine to reduce discomfort during injections. Specific techniques, such as linear retrograde and fanning methods, are advised for different areas of the face and body. The experts have also provided dosing guidelines and emphasize the need for individualized treatment plans. What do these results mean? The recommendations help practitioners use PDLLA more effectively and safely, providing better aesthetic outcomes for patients. Regular maintenance treatments are suggested every two years, with more frequent sessions for those with faster collagen loss. Proper training and careful patient screening are essential to avoid complications such as nodules or granulomas. [ABSTRACT FROM AUTHOR]

Voltage-gated potassium channels play a crucial role in cellular repolarization and are potential therapeutic targets in neuroinflammatory disorders and neurodegenerative diseases. This study explores Tityus bahiensis scorpion venom for neuroactive peptides. We identified the αKtx12 peptide as a potent neuroprotective agent. In SH-SY5Y cells, αKtx12 significantly enhances viability, validating its pharmacological potential. And in the animal model, we elucidate central nervous system (CNS) mechanism of αKtx12 through neuroproteomic analyses highlighting αKtx12 as a valuable tool for characterizing neuroplasticity and neurotropism, revealing its ability to elicit more physiological responses. The peptide's potential to promote cell proliferation and neuroprotection suggests a role in functional recovery from nervous system injury or disease. This research unveils the neuroactive potential of scorpion venom-derived αKtx12's, offering insights into its pharmacological utility. The peptide's impact on neuronal processes suggests a promising avenue for therapeutic development, particularly in neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Objective: Motor neuron disease (MND) is a group of neurological diseases, the majority being amyotrophic lateral sclerosis (ALS), with varying clinical presentations across demographics. Clinical trial enrollment reflecting global disease burden improves understanding of diverse presentations and aids personalized therapy development. We assessed the sex, racial, and ethnic composition of MND/ALS clinical trial participants relative to global disease burdens. Methods: We searched 'motor neuron disease OR amyotrophic lateral sclerosis' on ClinicalTrials.gov from 02/2000–04/2024. We extracted trial (start year, study site, sponsor location, phase, masking, intervention) and demographic data (sex, race, ethnicity) from randomized interventional studies. We obtained sex-based MND/ALS disease burden estimates from the Global Burden of Disease database. For females, we calculated pooled participation-to-prevalence ratio (PPR) with 95% confidence intervals (CIs), with PPR of 0.8–1.2 indicating adequate enrollment. We used Kruskal–Wallis tests to compare demographic groups across trial characteristics. Results: Of 85 trials, females comprised 37.47% (n = 5011) of 13,372 participants; the pooled female PPR was 0.97 (95% CI: 0.77–1.16). Of 41 trials (9340 participants) reporting race, 121 (1.30%) participants were Black or African American, 16 (0.17%) American Indian or Alaskan Native, and 6 (0.06%) Native Hawaiian or Other Pacific Islander. 24 trials (595 participants) reported ethnicity, with a minority of Hispanic participants (n = 153; 2.57%). Conclusions: MND/ALS clinical trials had adequate female enrollment relative to global disease burdens. Race and ethnicity data were underreported. However, there were enrollment disparities of racial and ethnic groups. Increased trial leadership diversity, equitable enrollment policies, and addressing barriers to participation could improve enrollment diversity. [ABSTRACT FROM AUTHOR]

Purpose: A cross-sectional study was conducted to investigate the feasibility of implementing routine collection of the Euro-Qol 5 dimensions (EQ-5D) questionnaire, to inform drug and health technology reimbursement decision making. Methods: Women with breast cancer were recruited during scheduled clinic visits to an academic cancer centre. EQ-5D-5L was self-administered using electronic tablets. Diagnostic and treatment data were abstracted from patient charts. Feasibility was assessed primarily by the proportion of patients who fully completed EQ-5D-5L and by their willingness to complete the instrument at each clinic visit. Results: 588 women were approached for study participation, 341 were enrolled. Fully completed EQ-5D-5L questionnaires were obtained in 323 participants (95% of participants, 95% CI 92–97%). Median time for EQ-5D-5L completion was 1.5 minutes (range:0.35 to 14.7). Mean age of participants was 58 years old. Most women who completed EQ-5D were White, born outside Canada and presented a high education level; one-quarter had metastatic disease. Most participants reported "No problems" in all EQ-5D-5L dimensions. Mean EQ-5D-5L index and mean EQ-5D-5L VAS values for all participants were respectively 0.83 (SD 0.13) and 75.7 (SD 17.45), with patients with metastatic disease scoring the lowest values. Seventy-eight percent of participants were willing to complete EQ-5D-5L at each clinic visit; lower Charlson comorbidity index and higher education level were predictors of willingness to continue to answer EQ-5D-5L. Conclusions: Tablet-based collection of EQ-5D-5L in the context of routine clinical practice proved to be feasible. However, many patients declined study participation or reported being in full health, raising concerns about whether this method of collecting EQ-5D adequately represents the health status of all breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Trimodulin (human polyvalent immunoglobulin [Ig] M ~ 23%, IgA ~ 21%, IgG ~ 56% preparation) has previously been associated with a lower mortality rate in a subpopulation of patients with severe community-acquired pneumonia on invasive mechanical ventilation (IMV) and with clear signs of inflammation. The hypothesis for the ESsCOVID trial was that trimodulin may prevent inflammation-driven progression of severe coronavirus disease 2019 (COVID-19) to critical disease or even death. Methods: Adults with severe COVID-19 were randomised to receive intravenous infusions of trimodulin or placebo for 5 consecutive days in addition to standard of care. The primary efficacy endpoint was a composite of clinical deterioration (Days 6–29) and 28-day all-cause mortality (Days 1–29). Results: One-hundred-and-sixty-six patients received trimodulin (n = 84) or placebo (n = 82). Thirty-three patients died, nine during the treatment phase. Overall, 84.9% and 76.5% of patients completed treatment and follow-up, respectively. The primary efficacy endpoint was reported in 33.3% of patients on trimodulin and 34.1% of patients on placebo (P = 0.912). No differences were observed in the proportion of patients recovered on Day 29, days of invasive mechanical ventilation, or intensive care unit-free days. Rates of treatment-emergent adverse events were comparable. A post hoc analysis was conducted in patients with early systemic inflammation by excluding those with high CRP (> 150 mg/L) and/or D-dimer (≥ 3 mg/L) and/or low platelet counts (< 130 × 109/L) at baseline. Forty-seven patients in the trimodulin group and 49 in the placebo group met these criteria. A difference of 15.5 percentage points in clinical deterioration and mortality was observed in favour of trimodulin (95% confidence interval: −4.46, 34.78; P = 0.096). Conclusion: Although there was no difference in the primary outcome in the overall population, observations in a subgroup of patients with early systemic inflammation suggest that trimodulin may have potential in this setting that warrants further investigation. ESsCOVID was registered prospectively at ClinicalTrials.gov on October 6, 2020.: NCT04576728 [ABSTRACT FROM AUTHOR]

This article examines the impact of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy on caregiver burden in individuals with essential tremor (ET). The study included 18 patients with medication-refractory ET and their caregivers. The results showed that MRgFUS thalamotomy not only reduced the need for caregiver assistance with daily tasks but also decreased caregiver burden. However, there was no significant change in ET-specific caregiver burden. The study suggests that caregiver burden in ET may be more influenced by caregivers' perception of patients' distress rather than solely by tremor severity. Further research with larger sample sizes and longer follow-up durations is needed to explore these findings. [Extracted from the article]

Knowing the properties of single photons produced in a Spontaneous Parametric Down-Conversion (SPDC) source can be crucial for specific applications and uses. In particular, the spectral properties are of key relevance. Here, we investigate a commercial SPDC source using our fast broadband spectrometer. Our analysis is a valid method for other SPDC sources, as well as other single-photon generation techniques, thus providing a good example of how to use this spectrometer design. We calibrate the spectrometer using known lines of the argon emission spectrum. We show that the two down-converted photons from the SPDC source have different spectral properties depending on the pump power, and under which condition we measured spectrally similar down-converted photons. Finally, we were able to reconstruct and investigate the spectral information for the pump photon. [ABSTRACT FROM AUTHOR]

The mitigation of damaged hair conditions involves the application and penetration of substances to stabilize broken bond sites, restore lipids and proteins, reinstate hydrophobicity, and recover hair mechanical properties. Vegetable oils, in general, exhibit a list of advantageous characteristics much desired by consumers, given the associated benefits for hair fibers. While coconut oil is highly popular in the hair care market and extensively studied for its ability to diffuse through the hair cortex, the effects of avocado and argan oil on the internal structure of hair and their potential benefits remain underexplored. Tensile and fatigue tests, as well as Raman spectroscopy, were carried out to investigate the interaction of these three oils with virgin and bleached Caucasian hair. The oils were applied in sufficient amounts directly to hair tresses and maintained for 24 h at 25 °C. Our results show that the three oils successfully diffused and interacted with the cortical region of the hairs. Their impact on hair mechanical properties depends on the level of damage and humidity conditions. In virgin hair, coconut and avocado oil reinforce the hydrophobic barrier of the cellular membrane complex, preventing water from causing intense perturbation of the mechanical properties, leading to increased stiffness and break stress. Meanwhile, due to the high degree of unsaturation of its fatty acid chains, argan oil increases water absorption, resulting in losses in hair resistance. When bleached, the hydrophilicity of the hair fiber increases, determining more affinity for argan oil. Consequently, the affinity with water is also elevated, causing increased fragility to mechanical stress. The analyzed vegetable oils are not always beneficial for hair care. Their specific chemical characteristics and hair conditions will influence the final results and should be taken into consideration in hair care product development. [ABSTRACT FROM AUTHOR]

Protists encompass a vast widely distributed group of organisms, surpassing the diversity observed in metazoans. Their diverse ecological niches and life forms are intriguing characteristics that render them valuable subjects for in-depth cell biology studies. Throughout history, viruses have played a pivotal role in elucidating complex cellular processes, particularly in the context of cellular responses to viral infections. In this comprehensive review, we provide an overview of the cellular alterations that are triggered in specific hosts following different viral infections and explore intricate biological interactions observed in experimental conditions using different host-pathogen groups. An in-depth review compiling information about the effects of virus infections in protists and discussing how these interactions are important for cell biology, ecology and biotechnology. [ABSTRACT FROM AUTHOR]

In the present study, an anodizing process was applied to aluminum alloy (AA2024-T3) to enhance interlocking in dissimilar joints with glass fiber-reinforced polyetherimide (GF/PEI) composite, using ytterbium-doped laser fiber welding as a heat source. A factorial Central Composite Design (CCD) was conducted to determine the most appropriate processing and optimization parameters, with lap shear strength (LSS) as the response variable. The obtained and fractured joints were characterized. Anodizing effectively improved the interlocking between dissimilar joints, resulting in LSS values of around 16 MPa. Surface impressions were observed in joints with lower shear values, likely due to the ineffective heat distribution in the processed joint. In the AA2024-T3 alloy, the annealing process occurred, beginning with the segregation of the alloy elements at the grain boundaries and subsequently reducing its hardness. The SEM analysis of the laminate in the best welding condition revealed a well-established fracture surface, with cusps, fibers covered by the polymer matrix, and river marks, indicating good consolidation of the process applied to the metal/polymer junction, which is consistent with the highest shear values obtained. These findings have important implications for future research and industrial applications and can help advance the understanding of these materials and processes. [ABSTRACT FROM AUTHOR]

This article discusses the use of deep brain stimulation (DBS) as a potential treatment for post-traumatic stress disorder (PTSD). PTSD is a psychiatric condition that affects a significant portion of the population and can be resistant to conventional therapies. DBS involves the implantation of electrodes into specific areas of the brain to modulate neural activity and has shown promising results in reducing PTSD symptoms in early studies. However, further research is needed to establish the efficacy of DBS for PTSD and to identify the most suitable candidates for the procedure. [Extracted from the article]

The phylum Nucleocytoviricota includes the largest and most complex viruses known. These "giant viruses" have a long evolutionary history that dates back to the early diversification of eukaryotes, and over time they have evolved elaborate strategies for manipulating the physiology of their hosts during infection. One of the most captivating of these mechanisms involves the use of genes acquired from the host—referred to here as viral homologs or "virologs"—as a means of promoting viral propagation. The best-known examples of these are involved in mimicry, in which viral machinery "imitates" immunomodulatory elements in the vertebrate defense system. But recent findings have highlighted a vast and rapidly expanding array of other virologs that include many genes not typically found in viruses, such as those involved in translation, central carbon metabolism, cytoskeletal structure, nutrient transport, vesicular trafficking, and light harvesting. Unraveling the roles of virologs during infection as well as the evolutionary pathways through which complex functional repertoires are acquired by viruses are important frontiers at the forefront of giant virus research. [ABSTRACT FROM AUTHOR]

Purpose: The primary aim of this study was to establish the reliability of candidate items as a step in the development of the Amyotrophic Lateral Sclerosis–Bulbar Dysfunction Index–Remote (ALS-BDI-Remote), a novel tool being developed for the detection and monitoring of bulbar signs and symptoms in remote settings. Method: The set of candidate items included 40 items covering three domains: cranial nerve examination, auditory-perceptual evaluation, and functional assessment. Forty-eight participants diagnosed with ALS and exhibiting a range of bulbar disease severity were included. Data collection for each participant took place on Zoom over three sessions. During Session 1, the participants were instructed to adjust their Zoom settings and to optimize their recording environment (e.g., lighting, background noise). Their cognition and eating were screened to determine their ability to follow instructions and their eligibility to perform the swallowing and chewing tasks. During Session 2, two speechlanguage pathologists (SLPs) administered the tool consecutively to determine the items’ interrater reliability. During Session 3, one of the SLPs readministered the tool within 2 weeks of Session 1 to assess test–retest reliability. The reliability of each item was estimated using weighted kappa and the percentage of agreement. To be considered reliable, the items had to reach a threshold of 0.5 weighted kappa or 80% percentage agreement (if skewed distribution of the scores) for both interrater and test–retest reliability. Results: In total, 33 of the 40 candidate items reached the reliability cutoff for both reliability analyses. All assessment domains included reliable items. Items requiring very good visualization of structures or movements were generally less reliable. Conclusions: This study resulted in the selection of reliable items to be included in the next version of the ALS-BDI-Remote, which will undergo psychometric evaluation (reliability, validity, and responsiveness analyses). Additionally, the results contributed to our understanding of the remote administration of SLP assessments for telehealth applications. [ABSTRACT FROM AUTHOR]

This work adheres to the recommendations for publication in three steps (Marin-Garcia, 2021). We propose a protocol to develop research the objective of which is to analyse the needs and challenges, as perceived by university lecturers, related to teaching, learning, or assessing competences related to the innovative capacity of students in an array of digital remote teaching contexts. In this sense, we want to consider situations where teachers watch their students interact with each other. The interaction between students can occur face-to-face or remotely and, in the latter case, either synchronous or asynchronous. In addition, teacher observation can be done synchronously (face-to-face or remotely) or by watching a previously recorded video. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. Results: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed. [ABSTRACT FROM AUTHOR]

Cultivated meat (CM) is a disruptive technology that provides an alternative to animal protein. In this context, the Amazon manatee (Trichechus inunguis) emerges as an important case. Although it is illegal to hunt this large mammal, its meat continues to be consumed, causing several threats to its natural habitat. The aim of this study is to explore the impacts of introducing the Amazon manatee CM into the traditional meat value chain as a tool to aid the biodiversity of the Amazon Basin. Thus, we developed a strengths, weaknesses, opportunities, and threats matrix from the content analysis of 11 interviews conducted between October 2021 and May 2022. The interviewees were experts in different fields, ranging from financial analysts of novel food technologies to biologists, researchers, and others. We presented the theme of illegal hunting and its consequences during the interviews, followed by the CM process, and explained how the royalties from the sale of this innovative product could help to preserve Amazon biodiversity through the proposal of a new business model. The main findings suggest that the proposed model would produce good results, but the threat of a rebound effect from the consumption of wild animals was mentioned in most responses, especially by actors involved in conservation. The strengths and opportunities of this disruptive narrative mainly focused on preserving biodiversity and promoting environmental awareness, combining the conservation of wildlife and the consumption of novel food. The weaknesses included the lack of knowledge and the non-existent market. This framework is relevant for policymakers, nongovernmental organizations, and researchers seeking to improve the sustainability not only of the species found in the Amazon, but also around the world. [ABSTRACT FROM AUTHOR]

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The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery. [ABSTRACT FROM AUTHOR]

This prospective, open-label trial (NCT04720469) screened 16 consecutive mrET patients who had undergone MRgFUS thalamotomy at least 1 year prior (MRgFUS SB 1 sb ). Herein, staged, bilateral MRgFUS thalamotomy was safe in a small sample of patients with mrET. Keywords: essential tremor; bilateral; thalamotomy; focused ultrasound; safety EN essential tremor bilateral thalamotomy focused ultrasound safety 1559 1561 3 10/24/23 20231001 NES 231001 Staged, open-surgical lesioning of the thalamic ventral intermediate nucleus to abate medication-refractory essential tremor (mrET) has been historically associated with a high frequency of adverse events (AEs), including speech and balance impairments.[1] More recently, the real-time imaging and thermometry guidance offered by magnetic resonance-guided focused ultrasound (MRgFUS) have allowed for minimally-invasive thalamotomies with increased focal accuracy to address upper limb tremor in ET patients.[2] Qualitative and semi-quantitative trials evaluating the safety of staged, bilateral MRgFUS thalamotomy have reported AEs that were mostly transient with mild to moderate severity based on patients' and physicians' perceived deficits.[[3], [5]] However, a comprehensive quantitative analysis of the potential post-thalamotomy changes in stance and gait balance (ie, equilibrium), and oro-motor function is lacking. We comprehensively evaluated the incidence and severity of AEs, including changes in equilibrium, speech, and cognition, following staged, bilateral MRgFUS thalamotomy for patients with mrET. [Extracted from the article]

Purpose: Early detection and tracking of bulbar dysfunction in amyotrophic lateral sclerosis (ALS) are critical for directing management of the disease. Existing physiological assessments of bulbar dysfunction are often inaccessible and cost-prohibitive for clinical application. Existing clinical assessments are limited. The overall goal of our research is to develop a brief and reliable, clinician-administered assessment tool, the ALS Bulbar Dysfunction Index (ALS-BDI) to evaluate bulbar dysfunction. The aim of this study was to establish content and face validity of the ALS-BDI through itemgeneration and reduction, including item scoring. Methods: The design of the ALS-BDI followed guidelines outlined by the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The design stage of the ALS-BDI involved two steps: (Step 1) the generation of candidate items from a literature review of commonly used clinical tools, and selection of items following a review of item reliability and item relevance and expert consensus; (Step 2) the assessment of their content and face validity via online survey feedback from experts (n = 35). The initial design was followed by a semi-structured cognitive interview with Speech-Language Pathologists (n = 5) to finalize a testable draft of the instrument. Results: Two drafts of the ALS-BDI were developed. The first draft contained 48 items, after a review of existing clinical tools for their relevance to bulbar dysfunction in ALS. Of the 48 items, 35 items were retained after surveying experts and clinician users for their relevance, feasibility, interpretability, and appropriateness. The second draft of the ALS-BDI contained 37 items, due to one item splitting, based on users cognitive interviews. Conclusions: The ALS-BDI described in this study aims to provide a brief and reliable, clinician-administered assessment tool to evaluate bulbar dysfunction in patients with ALS. Future research will evaluate the psychometric properties of this tool including its reliability, validity, and responsiveness to change over time. [ABSTRACT FROM AUTHOR]

Presynaptic modulation is a fundamental process regulating synaptic transmission. Striatal indirect pathway projections originate from A2A‐expressing spiny projection neurons (iSPNs), targeting the globus pallidus external segment (GPe) and control the firing of the tonically active GPe neurons via GABA release. It is unclear if and how the presynaptic G‐protein‐coupled receptors (GPCRs), GABAB and CB1 receptors modulate iSPN‐GPe projections. Here we used an optogenetic platform to study presynaptic Ca2+ and GABAergic transmission at iSPN projections, using a genetic strategy to express the calcium sensor GCaMP6f or the excitatory channelrhodopsin (hChR2) on iSPNs. We found that P/Q‐type calcium channels are the primary voltage‐gated Ca2+ channel (VGCC) subtype controlling presynaptic calcium and GABA release at iSPN‐GPe projections. N‐type and L‐type VGCCs also contribute to GABA release at iSPN‐GPe synapses. GABAB receptor activation resulted in a reversible inhibition of presynaptic Ca2+ transients (PreCaTs) and an inhibition of GABAergic transmission at iSPN‐GPe synapses. CB1 receptor activation did not inhibit PreCaTs but inhibited GABAergic transmission at iSPN‐GPe projections. CB1 effects on GABAergic transmission persisted in experiments where NaV and KV1 were blocked, indicating a VGCC‐ and KV1‐independent presynaptic mechanism of action of CB1 receptors. Taken together, presynaptic modulation of iSPN‐GPe projections by CB1 and GABAB receptors is mediated by distinct mechanisms. Key points: P/Q‐type are the predominant voltage‐gated Ca2+ channels controlling presynaptic Ca2+ and GABA release on the striatal indirect pathway projections.GABAB receptors modulate iSPN‐GPe projections via a VGCC‐dependent mechanism.CB1 receptors modulate iSPN‐GPe projections via a VGCC‐independent mechanism. [ABSTRACT FROM AUTHOR]

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson's disease. The performance of the clinical MRgFUS system's cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20–0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases. [ABSTRACT FROM AUTHOR]

Purpose: Facial movement analysis during facial gestures and speech provides clinically useful information for assessing bulbar amyotrophic lateral sclerosis (ALS). However, current kinematic methods have limited clinical application due to the equipment costs. Recent advancements in consumer-grade hardware and machine/deep learning made it possible to estimate facial movements from videos. This study aimed to establish the clinical validity of a video-based facial analysis for disease staging classification and estimation of clinical scores. Method: Fifteen individuals with ALS and 11 controls participated in this study. Participants with ALS were stratified into early and late bulbar ALS groups based on their speaking rate. Participants were recorded with a three-dimensional (3D) camera (color + depth) while repeating a simple sentence 10 times. The lips and jaw movements were estimated, and features related to sentence duration and facial movements were used to train a machine learning model for multiclass classification and to predict the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) bulbar subscore and speaking rate. Results: The classification model successfully separated healthy controls, the early ALS group, and the late ALS group with an overall accuracy of 96.1%. Video-based features demonstrated a high ability to estimate the speaking rate (adjusted R² = .82) and a moderate ability to predict the ALSFRS-R bulbar subscore (adjusted R² = .55). Conclusions: The proposed approach based on a 3D camera and machine learning algorithms represents an easy-to-use and inexpensive system that can be included as part of a clinical assessment of bulbar ALS to integrate facial movement analysis with other clinical data seamlessly. [ABSTRACT FROM AUTHOR]

Mucoepidermoid carcinomas (MECs) are a form of salivary gland malignancy. They are classified according to histological grade and perineural invasion (PNI). In another cancer subtypes, positive-PNI suggests increased poor prognosis; however, the role of isolated positive-PNI salivary gland MEC can still be better investigated as a risk factor. This study investigated whether isolated PNI is independently associated with poor outcomes. Retrospective study, cohort case-series, single-center hospital from 2009 to 2019. Patient demographics, primary tumor, intervention, and survival data are included. Univariate, multivariate, and Kaplan–Meier survival curve analyses were used for comparison.The study group consisted of 32 patients (15 PNI-positive tumors, and 17 PNI-negative tumors), all admitted for surgery. Univariate analysis showed differences in grade (p = 0.038), positive margins (p = 0.034), soft tissue invasion (p < 0.001), pathological stage (p = 0.014), recurrence (p = 0.015), distant metastasis (p = 0.015) and MEC related death (p = 0.015). The risk in PNI-positive patients to develop soft tissue invasion and positive surgical margins was OR = 8.57 and OR = 4.88, respectively. Multivariate analysis found age differences (p = 0.038), with OR = 1.08. The Disease Specific Survival (DSS) was worst in the PNI-positive group (log-rank p-value = 0.0011), where the probability of dying occurred in the 12–24 months period (log-rank p-value = 0.002). PNI-positive salivary gland MEC is an independent prognostic factor, with poor DSS, increased locoregional recurrence, close correlation with a more aggressive pattern of the disease, and should be reviewed as a high grade histological criteria. Our findings may imply changes in the clinical approach with a more aggressive attitude in the overall treatment. [ABSTRACT FROM AUTHOR]

The incidence of amyotrophic lateral sclerosis in Ohio 2016-2018: the Ohio population-based ALS Registry. Environmental and occupational risk factors of amyotrophic lateral sclerosis: a population-based case-control study. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. [Extracted from the article]

Purpose: Tauopathy and transactive response DNA binding protein 43 (TDP43) proteinopathy are associated with neurodegenerative diseases. These proteinopathies are difficult to detect in vivo. This study examined if spectral-domain optical coherence tomography (SD-OCT) can differentiate in vivo the difference in peripapillary retinal nerve fibre layer (pRNFL) thickness and macular retinal thickness between participants with presumed tauopathy (progressive supranuclear palsy) and those with presumed TDP43 proteinopathy (amyotrophic lateral sclerosis and semantic variant primary progressive aphasia). Study design: Prospective, multi-centre, observational study. Materials and methods: pRNFL and macular SD-OCT images were acquired in both eyes of each participant using Heidelberg Spectralis SD-OCT. Global and pRNFL thickness in 6 sectors were analyzed, as well as macular thickness in a central 1 mm diameter zone and 4 surrounding sectors. Linear mixed model methods adjusting for baseline differences between groups were used to compare the two groups with respect to pRNFL and macular thickness. Results: A significant difference was found in mean pRNFL thickness between groups, with the TDP-43 group (n = 28 eyes) having a significantly thinner pRNFL in the temporal sector than the tauopathy group (n = 9 eyes; mean difference = 15.46 µm, SE = 6.98, p = 0.046), which was not significant after adjusting for multiple comparisons. No other significant differences were found between groups for pRNFL or macular thickness. Conclusion: The finding that the temporal pRNFL in the TDP-43 group was on average 15.46 µm thinner could potentially have clinical significance. Future work with larger sample sizes, longitudinal studies, and at the level of retinal sublayers will help to determine the utility of SD-OCT to differentiate between these two proteinopathies. [ABSTRACT FROM AUTHOR]

Background: GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery.Methods: This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations.Results: BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08.Conclusions: Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Endovascular therapeutic hypothermia (ETH) reduces the damage by ischemia/reperfusion cell syndrome in cardiac arrest and has been studied as an adjuvant therapy to percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). New available advanced technology allows cooling much faster, but there is paucity of resources for training to avoid delays in door-to-balloon time (DTB) due to ETH and subsequently coronary reperfusion, which would derail the procedure. The aim of the study was to describe the process for the development of a simulation, training & educational protocol for the multidisciplinary team to perform optimized ETH as an adjunctive therapy for STEMI. Methods and results: We developed an optimized simulation protocol using modern mannequins in different realistic scenarios for the treatment of patients undergoing ETH adjunctive to PCI for STEMIs starting from the emergency room, through the CathLab, and to the intensive care unit (ICU) using the Proteus® Endovascular System (Zoll Circulation Inc™, San Jose, CA, USA). The primary endpoint was door-to-balloon (DTB) time. We successfully trained 361 multidisciplinary professionals in realistic simulation using modern mannequins and sham situations in divisions of the hospital where real patients would be treated. The focus of simulation and training was logistical optimization and educational debriefing with strategies to reduce waste of time in patient's transportation from different departments, and avoiding excessive rewarming during transfer. Afterwards, the EHT protocol was successfully validated in a trial randomizing 50 patients for 18 minutes cooling before coronary recanalization at the target temperature of 32 ± 1.0 0C or PCI-only. A total of 35 patients underwent ETH (85.7% [30/35] in 90 ± 15 minutes), without delays in the mean door-to-balloon time for primary PCI when compared to 15 control group patients (92.1 minutes versus 87 minutes, respectively; p = 0.509). Conclusions: Realistic simulation, intensive training and educational debriefing for the multidisciplinary team propitiated feasible endovascular therapeutic hypothermia as an adjuvant therapy to primary PCI in STEMI. ClinicalTrials.gov: NCT02664194. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy (CTX) has historically been the primary treatment for advanced urothelial cancer (aUC), with limited alternative options. The therapeutic landscape experienced a paradigm shift following the results of the EV-302 and Checkmate-901 trials, which led to the approval of Enfortumab vedotin plus pembrolizumab (EV-P) as the preferred first-line treatment, and nivolumab plus CTX for those unable to receive the preferred regimen. Currently, further investigations are underway to explore PD-1 and PD-L1 inhibitors in the initial treatment of aUC. We conducted a systematic search across PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) comparing immune checkpoint inhibitors (ICI)-CTX combinations versus CTX alone as first-line treatment for advanced UC. Employing a random-effects model, we pooled hazard ratios (HR) with 95% confidence intervals (CI). Our analysis encompassed 3 RCTs, involving 2162 participants, with 51.16% randomized to combination therapy with platinum-based CTX. Compared to CTX alone, immune-chemotherapy significantly improved overall survival (HR 0.84; 95% CI 0.75-0.93; P <.01), progression-free survival (HR 0.78; 95% CI 0.70-0.86; P <.01), and objective response rate (RR 1.20; 95% CI 1.06-1.36; P <.01), while elevating the risk of immune-related adverse events (P -value =.02). In this meta-analysis of RCTs, ICI plus CTX demonstrated a significant association with improved survival at the expense of an increased risk of immune-related adverse events. Therefore, our findings suggest that this combination should be considered as an initial treatment for aUC in platinum-eligible patients who cannot receive EV-P. This meta-analysis investigates immune checkpoint inhibitors (ICI) combined with platinum-based chemotherapy (CTX) as a first-line treatment for advanced urothelial cancer (aUC). Analyzing data from three randomized controlled trials with 2162 patients, the study demonstrates that ICI-CTX improve overall survival, progression-free survival, and response rates. These findings support the consideration of ICI-CTX as an initial treatment option for platinum-eligible aUC patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Patients with recurrent squamous cell carcinoma of the head and neck (rHNC) face an aggressive disease. Surgical resection is the gold standard treatment. Immediate adjuvant post-operative stereotactic ablative radiotherapy (PO-SABR) for rHNC is debatable. Materials and Methods: We retrospectively identified patients who were treated with PO-SABR at the AC Camargo Cancer Center, Brazil. Results: Eleven patients were treated between 2018 and 2021. The median time between salvage surgery and PO-SABR was 31 days (range, 25–42) and the median PO-SABR total dose was 40 Gy (range, 30–48 Gy). The 2-and 4-year actuarial DFS were 62.3% and 41.6%, while the 2-and 4-year OS probabilities were 80.0% and 53.3%, respectively. Eight (72.7%) patients were alive and six (54.5%) were without disease at the last follow-up. Two (18.1%) patients had local failure in the PO-SABR field. Three (27.3%) patients had distant metastasis, diagnosed in a median time of 9 months (range, 4–13) after completion of PO-SABR. On univariate analysis, predictive factors related to worse OS were: interval between previous radiotherapy and PO-SABR ≤ 24 months (p = 0.033) and location of the salvage target in the oral cavity (p = 0.013). The total dose of PO-SABR given in more than three fractions was marginally statistically significant, favoring the OS (p = 0.051). Conclusions: Our results encourage the use of a more aggressive approach in selected patients with rHNC by combining salvage surgery with immediate PO-SABRT, but this association needs to be further explored. [ABSTRACT FROM AUTHOR]

Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). Results: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration. [ABSTRACT FROM AUTHOR]

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Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?Methods/design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery.Results: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners.Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions. [ABSTRACT FROM AUTHOR]

Coronavirus has emerged as a global health threat due to its accelerated geographic spread over the last two decades. This article reviews the current state of knowledge concerning the origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Historically, it has caused two pandemics: severe acute respiratory syndrome and Middle East respiratory syndrome followed by the present COVID-19 that emerged from China. The virus is believed to be acquired from zoonotic source and spreads through direct and contact transmission. The symptomatic phase manifests with fever, cough and myalgia to severe respiratory failure. The diagnosis is confirmed using reverse transcriptase PCR. Management of COVID-19 is mainly by supportive therapy along with mechanical ventilation in severe cases. Preventive strategies form the major role in reducing the public spread of virus along with successful disease isolation and community containment. Development of a vaccine to eliminate the virus from the host still remains an ongoing challenge. [ABSTRACT FROM AUTHOR]

Background: Remote health monitoring with wearable sensor technology may positively impact patient self-management and clinical care. In individuals with complex health conditions, multi-sensor wear may yield meaningful information about health-related behaviors. Despite available technology, feasibility of device-wearing in daily life has received little attention in persons with physical or cognitive limitations. This mixed methods study assessed the feasibility of continuous, multi-sensor wear in persons with cerebrovascular (CVD) or neurodegenerative disease (NDD). Methods: Thirty-nine participants with CVD, Alzheimer's disease/amnestic mild cognitive impairment, frontotemporal dementia, Parkinson's disease, or amyotrophic lateral sclerosis (median age 68 (45–83) years, 36% female) wore five devices (bilateral ankles and wrists, chest) continuously for a 7-day period. Adherence to device wearing was quantified by examining volume and pattern of device removal (non-wear). A thematic analysis of semi-structured de-brief interviews with participants and study partners was used to examine user acceptance. Results: Adherence to multi-sensor wear, defined as a minimum of three devices worn concurrently, was high (median 98.2% of the study period). Non-wear rates were low across all sensor locations (median 17–22 min/day), with significant differences between some locations (p = 0.006). Multi-sensor non-wear was higher for daytime versus nighttime wear (p < 0.001) and there was a small but significant increase in non-wear over the collection period (p = 0.04). Feedback from de-brief interviews suggested that multi-sensor wear was generally well accepted by both participants and study partners. Conclusion: A continuous, multi-sensor remote health monitoring approach is feasible in a cohort of persons with CVD or NDD. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development. Methods: A literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data. Results: The search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS. Conclusion: BCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Oral diadochokinesis (DDK) is a standard dysarthria assessment task. To extract automatic and semi-automatic DDK measurements, numerous DDK analysis algorithms based on acoustic signal processing are available, including amplitude based, spectral based, and hybrid. However, these algorithms have been predominantly validated in individuals with no perceptible to mild dysarthria. The behavior of these algorithms across dysarthria severity is largely unknown. Likewise, these algorithms have not been tested equally for various syllable types. The goal of this study was to evaluate the performance of five common DDK algorithms as a function of dysarthria severity, considering syllable types. Method: We analyzed 282 DDK recordings of /ba/, /pa/, and /ta/ from 145 participants with amyotrophic lateral sclerosis. Recordings were stratified into mild, moderate, or severe dysarthria groups based on individual performance on the Speech Intelligibility Test. Analysis included manual and automatic estimation of the number of syllables, DDK rate, and cycle-to-cycle temporal variability (cTV). Validation metrics included Bland–Altman mixed-effects limits of agreement between manual and automatic syllable counts, recall and precision between manual and automatic syllable boundary detection, and Kendall’s tau-b correlations between manual and algorithm-detected DDK rate and cTV. Results: The amplitude-based algorithm (absolute energy) yielded the strongest correlations with manual analysis across all severity groups for DDK rate (τb = 0.7–0.84) and cTV (τb = 0.7–0.84) and the narrowest limits of agreement (−5.92 to 7.12 syllable difference). Moreover, this algorithm also provided the highest mean recall and precision across severity groups for /ba/ and /pa/, but with significantly more variation for/ta/. Conclusions: Algorithms based on signal energy analysis appeared to be the most robust for DDK analysis across dysarthria severity and syllable types; however, it remains prone to error against severe dysarthria and alveolar syllable context. Further development is needed to address this important issue. [ABSTRACT FROM AUTHOR]