Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.

OBJECTIVE: No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS. METHODS: This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher\u27s exact, and χ RESULTS: Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p \u3c 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p \u3e 0.05). INTERPRETATION: Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Combined Respiratory Training to Improve Pulmonary and Cough Function in Persons with ALS

Lay Abstract. All persons with amyotrophic lateral sclerosis (pALS) experience worsening of breathing and cough function as the disease progresses. Impairments in breathing and the inability to clear the airway contribute to respiratory infections, pneumonia, hospitalizations, and reduced quality of life. Currently, the use of prescription respiratory devices are recommended to maintain pulmonary health and reduce the risk of lung infections in pALS. However, these respiratory devices are typically prescribed reactively once significant impairment in function has already occurred. There are currently no effective, proactive interventions to help prevent deterioration of cough and breathing function in pALS. Therefore, identification of simple, accessible breathing exercises that can be performed immediately following ALS diagnosis is a priority to improve current clinical care for all pALS. We propose that the use of a combined respiratory strength training exercise program will improve breathing and cough function in pALS. Thirty-nine pALS with mild disease severity will complete lung volume recruitment and expiratory muscle strength training exercises daily for five weeks. Both lung volume recruitment and expiratory muscle strength training have been studied independently in pALS and shown to be safe, feasible, and effective in improving respiratory and cough measurements. The goal of this study is to combine these exercise regimens to improve two very important measures of respiratory function and airway clearance: forced vital capacity and peak cough flow. We will also assess how the exercise regimen impacts pALS-reported shortness of breath, exercise therapy burden and quality of life. The proposed combined respiratory training regimen represents an improvement from the current standard of care for the following reasons: 1. Training will be implemented early in the disease to capitalize on and maintain respiratory function and cough strength; 2. Training equipment is accessible, inexpensive and easy-touse; and 3. Training initiation does not require insurance approval or shipment of disposable replacement parts. The proposed study represents an opportunity to intervene proactively and empowers pALS with a tool to combat the loss of function early in the disease process. If successful, this combined training has the potential to improve the trajectory of decline in breathing and cough functions, ultimately prolonging survival in pALS

Diagnostic utility of the amyotrophic lateral sclerosis Functional Rating Scale-Revised to detect pharyngeal dysphagia in individuals with amyotrophic lateral sclerosis.

ObjectiveThe ALS Functional Rating Scale-Revised (ALSFRS-R) is the most commonly utilized instrument to index bulbar function in both clinical and research settings. We therefore aimed to evaluate the diagnostic utility of the ALSFRS-R bulbar subscale and swallowing item to detect radiographically confirmed impairments in swallowing safety (penetration or aspiration) and global pharyngeal swallowing function in individuals with ALS.MethodsTwo-hundred and one individuals with ALS completed the ALSFRS-R and the gold standard videofluoroscopic swallowing exam (VFSE). Validated outcomes including the Penetration-Aspiration Scale (PAS) and Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) were assessed in duplicate by independent and blinded raters. Receiver operator characteristic curve analyses were performed to assess accuracy of the ALSFRS-R bulbar subscale and swallowing item to detect radiographically confirmed unsafe swallowing (PAS > 3) and global pharyngeal dysphagia (DIGEST >1).ResultsAlthough below acceptable screening tool criterion, a score of ≤ 3 on the ALSFRS-R swallowing item optimized classification accuracy to detect global pharyngeal dysphagia (sensitivity: 68%, specificity: 64%, AUC: 0.68) and penetration/aspiration (sensitivity: 79%, specificity: 60%, AUC: 0.72). Depending on score selection, sensitivity and specificity of the ALSFRS-R bulbar subscale ranged between 34-94%. A score of ConclusionsThe ALSFRS-R bulbar subscale or swallowing item did not demonstrate adequate diagnostic accuracy to detect radiographically confirmed swallowing impairment. These results suggest the need for alternate screens for dysphagia in ALS