Recent Advances in Understanding the Molecular Mechanisms of SGLT2 Inhibitors in Atrial Remodeling.

Atrial cardiomyopathy and remodeling play pivotal roles in the development of atrial fibrillation (AF) and heart failure (HF), involving complex changes in atrial structure and function. These changes facilitate the progression of AF and HF by creating a dynamic interplay between mechanical stress and electrical disturbances in the heart. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for the management of type 2 diabetes, have demonstrated promising cardiovascular benefits, being currently one of the cornerstone treatments in HF management. Despite recent data from randomized clinical trials indicating that SGLT2is may significantly influence atrial remodeling, their overall effectiveness in this context is still under debate. Given the emerging evidence, this review examines the molecular mechanisms through which SGLT2is exert their effects on atrial remodeling, aiming to clarify their potential benefits and limitations. By exploring these mechanisms, this review aims to provide insights into how SGLT2is can be integrated into strategies for preventing the progression of atrial remodeling and HF, as well as the development of AF.

Clinical Features of Essential Voice Tremor and Associations with Tremor Severity and Response to Octanoic Acid Treatment.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to characterize the clinical features, tremor variability, and factors related to octanoic acid (OA) treatment response in essential voice tremor (EVT). STUDY DESIGN: Prospective, double blind, placebo-controlled, crossover study with secondary analysis. METHODS: Clinical tremor features in 16 individuals with EVT were comprehensively assessed, and correlations with acoustic tremor severity were determined. Intrasubject and intersubject variability measures were analyzed from 18 repeated measures for each acoustic tremor variable. Clinical correlates of treatment response were evaluated, and cumulative effects over a 2-week period of OA drug dosing were assessed. RESULTS: Participants with EVT were 90% female with a mean age of 70.31 (±8.68) years at the time of testing. Neurologist-rated body tremor beyond the vocal tract region was present in 69% of participants, and multiple vocal tract regions contributed to the voice tremor. The mean frequency of amplitude tremor was 4.67 Hz (±0.88). Respiratory tremor was evident in 50% of participants. Participants experienced moderate voice-related disability as assessed on the Voice Handicap Index-10 (19.38, ±8.50), and increased speaking effort. Acoustic tremor severity was significantly associated with severity of tremor affecting vocal tract structures. Overall intrasubject consistency was strong (single measures intraclass correlation coefficient = 0.701, P < .01), with high intersubject variability. Acoustic tremor severity was significantly, positively associated with treatment response, and results suggested a cumulative OA benefit for magnitude of amplitude tremor. CONCLUSIONS: This study identified common clinical correlates of EVT and demonstrated positive associations between acoustic tremor severity, severity of affected vocal tract structures, and response to treatment. LEVEL OF EVIDENCE: 2 Laryngoscope, 131:E2792-E2801, 2021.

The oral microbiome of early stage Parkinson's disease and its relationship with functional measures of motor and non-motor function.

Changes in the function and microbiome of the upper and lower gastrointestinal tract have been documented in Parkinson's disease (PD), although most studies have examined merely fecal microbiome profiles and patients with advanced disease states. In the present study we sought to identify sensitive and specific biomarkers of changes in the oral microbiome of early stage PD through shotgun metatranscriptomic profiling. We recruited 48 PD subjects and 36 age- and gender-matched healthy controls. Subjects completed detailed assessments of motor, cognitive, balance, autonomic and chemosensory (smell and taste) functions to determine their disease stage. We also obtained a saliva sample for profiling of microbial RNA and host mRNA using next generation sequencing. We found no differences in overall alpha and beta diversity between subject groups. However, changes in specific microbial taxa were observed, including primarily bacteria, but also yeast and phage. Nearly half of our findings were consistent with prior studies in the field obtained through profiling of fecal samples, with others representing highly novel candidates for detection of early stage PD. Testing of the diagnostic utility of the microbiome data revealed potentially robust performance with as few as 11 taxonomic features achieving a cross-validated area under the ROC curve of 0.90 and overall accuracy of 84.5%. Bioinformatic analysis of 167 different metabolic pathways supported shifts in a small set of distinct pathways involved in amino acid and energy metabolism among the organisms comprising the oral microbiome. In parallel with the microbial analysis, we also examined the evidence for changes in human salivary mRNAs in the same subjects. This revealed significant changes in a set of 9 host mRNAs, several of which mapped to various brain functions and showed correlations with some of the significantly changed microbial taxa. Unexpectedly, we also observed robust correlations between many of the microbiota and functional measures, including those reflecting cognition, balance, and disease duration. These results suggest that the oral microbiome may represent a highly-accessible and informative microenvironment that offers new insights in the pathophysiology of early stage PD.

The Effect of Octanoic Acid on Essential Voice Tremor: A Double-Blind, Placebo-Controlled Study.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to determine the effects of octanoic acid on acoustic, perceptual, and functional aspects of essential voice tremor (EVT). STUDY DESIGN: Prospective, double-blind, placebo-controlled, crossover study. METHODS: Sixteen participants with a diagnosis of EVT were randomized to a 3-week dosing condition of octanoic acid or placebo, followed by a 2-week washout period and crossover to the other condition for an additional 3 weeks. Baseline and post-testing sessions were completed before and at the completion of each condition. Primary outcome measures were the magnitude of amplitude and frequency tremor, measured from the acoustic signal. Secondary outcomes were auditory-perceptual ratings of tremor severity and self-ratings of voice handicap. RESULTS: Magnitude of amplitude and frequency tremor were significantly lower after 3 weeks of octanoic acid dosing as compared to the placebo condition. Auditory-perceptual ratings of tremor severity did not show significant differences between conditions. A trend toward better voice was seen for the sustained vowel ratings, but not the sentence-level ratings. No significant differences between conditions were seen on self-reported voice disability as assessed on the Voice Handicap Index-10. CONCLUSIONS: The results of this controlled investigation support the potential utility of octanoic acid for reducing the magnitude of tremor in people with EVT. Further research is needed to determine whether different dosing or treatment combinations can improve functional communication in EVT. LEVEL OF EVIDENCE: 1 Laryngoscope, 129:1882-1890, 2019.

The effect of anchors on reliability of endoscopic tremor ratings.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to determine the effects of anchors and training on intrarater and inter-rater reliability for visual-perceptual, endoscopic tremor ratings. STUDY DESIGN: Prospective cohort study. METHODS: Nasoendoscopy recordings of 10 participants with a diagnosis of essential voice tremor were evaluated by five voice specialists using the Vocal Tremor Scoring System. Ratings were performed before, immediately after, and 4 weeks after implementation of a training program with anchor stimuli. Immediate and long-term post-training ratings were performed with simultaneous use of anchor samples for each rating. RESULTS: Intrarater reliability showed significant improvement from pretraining to immediate and long-term post-training. Mean correlation coefficients (Spearman's rho) increased from 0.71 at pretraining to 0.84 and 0.90 at immediate and long-term post-training, respectively. Inter-rater reliability was not affected by training with anchors, with mean correlation coefficients ranging from 0.62 at pretraining to 0.58 and 0.64 at immediate and long-term post-training, respectively. CONCLUSIONS: Consistent, reproducible ratings are critical for the interpretation and comparison of endoscopic tremor data. Reliability findings from this study indicate that the use of anchor samples as referents for making ordinal judgments about the severity of tremor in oropharyngeal and laryngeal regions was helpful for improving internal standards and consistency but less useful for calibrating across different raters. LEVEL OF EVIDENCE: 4 Laryngoscope, 2016 127:411-416, 2017.

Assessment of disease progression and functional benefit in neurodegenerative disease: can we tell the difference?

Therapeutic strategies for neurodegenerative diseases include modalities intended to modulate disease progression as well as those whose intent is to improve or maintain functional capacity. As the search for pharmacodynamic markers has proved elusive, treatment outcomes most commonly reflect patient function. As a result, even when clinical trials show a beneficial effect, the underlying etiology of that benefit can be difficult to determine. This review summarizes recent trials in ALS and Parkinson's disease, with the goal of increasing understanding of how the choice of outcome measures influences what can be concluded from the results. Although most ALS trials have been negative in recent years, outcomes are reviewed in terms of potential conclusions that could have been drawn. Functional benefit has been established in a number of recent trials; however, the outcomes used have lead to uncertainty as to whether specific agents modify disease or alter function. In the absence of specific markers sensitive to alteration of disease specific pathways, the distinction between agents that alter underlying disease versus those that affect function may depend on underlying hypotheses rather than clinical trial results.