Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Arytenoid mucosal injury in young Thoroughbred horses 14 investigation of a proposed aetiology and clinical significance

AIM: To determine whether trauma to the larynx caused by nasotracheal intubation induced mucosal ulceration of the arytenoid cartilages of adult horses, and to determine the incidence of such ulceration in yearling Thoroughbred horses and its effect on athletic performance. METHODS: Laryngeal trauma was induced in a group of 21 adult horses by introduction of a nasogastric tube into the trachea three times within 5 min. Injury to the arytenoid cartilages or vocal cords was subjectively assessed immediately after intubation, and thereafter at weekly intervals for 10 weeks. The outcome and athletic performance of 33 Thoroughbred yearling horses with idiopathic disease of the arytenoid cartilages, diagnosed at the yearling sales, were evaluated and compared to those of control horses of the same gender and age, from the same sale. \ud RESULTS: Mucosal injury was noted immediately after intubation in every horse. Evidence of injury to the vocal or corniculate processes of the arytenoid cartilages or vocal cords was still apparent in 10/21 (48%) horses 1 week after intubation, five of which developed persistent lesions that remained present and unchanged from 28 days following intubation until the end of the 10-week observation period. All persistent lesions were nodules or focal swellings of the vocal cords or arytenoid cartilages, and there was no evidence of mucosal ulceration, infection or discharge. Mucosal ulceration of the vocal processes was the most common abnormality detected in the yearlings, affecting 16/33 (48%) that were diagnosed with idiopathic arytenoid disease at the yearling sales. Five of the 33 (15%) horses were diagnosed with arytenoid chondritis at the time of sale and were excluded from the performance outcome analysis. Of the 28 horses diagnosed with arytenoid abnormalities excluding chondritis, 19 (68%) raced with no history of respiratory-related problems, two (7%) were subsequently diagnosed with laryngeal hemiplegia, and seven (25%) were lost to follow-up. The case animals were 2.7 times more likely to race than control horses, but there was no difference between cases and controls in the likelihood of starting more than three times. CONCLUSIONS: This study showed that nasotracheal intubation in adult horses could result in immediate mucosal trauma, persistent swelling, and focal scarring of the arytenoid cartilages, but this did not mimic mucosal ulceration or chondritis of the arytenoid cartilages observed in yearling Thoroughbred horses. The population studied, however, may not accurately represent the population in which idiopathic disease occurs. In this study, arytenoid mucosal ulceration detected at sale did not commonly progress to arytenoid chondritis. However, a study of a larger population of horses with untreated, naturally occurring disease is required to confirm these findings. CLINICAL RELEVANCE: It is unlikely that trauma from nasogastric intubation caused arytenoid mucosal ulceration, therefore this procedure should not necessarily be discouraged. This study did not find evidence that horses diagnosed with arytenoid mucosal ulceration at yearling sales had a reduced performance history, therefore it is reasonable to continue to pass horses with uncomplicated arytenoid mucosal ulceration during post-sale endoscopic examination. However, monitoring of the lesions and treatment, if required, may be indicated in the post-sale period