SummaryInduced pluripotent stem cells (iPSCs) provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in vitro directed differentiation. Using iPSCs generated from a cohort carrying mutations (PiZZ) in the gene responsible for alpha-1 antitrypsin (AAT) deficiency, we find that the global transcriptomes of PiZZ iPSCs diverge from normal controls upon differentiation to hepatic cells. Expression of 135 genes distinguishes PiZZ iPSC-hepatic cells, providing potential clues to liver disease pathogenesis. The disease-specific cells display intracellular accumulation of mutant AAT protein, resulting in increased autophagic flux. Furthermore, we detect beneficial responses to the drug carbamazepine, which further augments autophagic flux, but adverse responses to known hepatotoxic drugs. Our findings support the utility of iPSCs as tools for drug development or prediction of toxicity.

H istorically, skiing as a form of locomotion was instrumental in activities such as hunting, medical transportation, and military conflict. It was not until the early 1800's that skiing became popular as a means of exercise, and it would take nearly 100 years to be adapted as a sport. 34 Alpine ski racing became an Olympic sport in 1936, and the first International Ski Federation (FIS) World Cup race was held in 1967. 16 Alpine skiing is now well organized, with competitions ranging from junior through masters levels. Although recreational skiing injuries have been well described, there is less published work on injuries sustained during alpine ski racing. The forces, speeds, and slope conditions that ski racers encounter differ greatly from the average recreational skier. 14,53 The purpose of this article is to comprehensively review the existing literature with regard to alpine ski racing injuries and to identify further areas of study and potential strategies for injury prevention. Methods A review of the published literature from 1976 to 2018 pertaining to alpine ski racing injuries was performed. Pertinent articles were identified from PubMed, Ovid, and Google Scholar using the search terms "ski racing," "alpine ski racing," "injury," and "epidemiology." Additional studies, including studies regarding specific ski racing injuries, were identified from the references of relevant articles. Studies focused on snowboarding injuries or on recreational alpine skiing injuries were excluded. epideMiology Reported injury rates in alpine skiing are high. 2,9,11,15,28,36,51,56 At the World Cup level, which is the highest level of competition, the incidence of injury ranges from 23.5 to 36.7 injuries per 100 athletes per season. 15,19,28 Nearly half (45.0%) of injuries in World Cup athletes occur during competition 15,19 as opposed to 825842S PHXXX10.

Joint space width (JSW), measured as the distance between the femoral and tibial subchondral bone margins on two-dimensional weight-bearing radiographs, is the initial imaging modality used in clinical settings to diagnose and evaluate the progression of osteoarthritis (OA). While, JSW is the only structural outcome approved by the FDA for studying the treatment of this disease in phase III clinical trials, recent reports suggest that magnetic resonance imaging (MRI)-based measurements of OA changes are superior due to increased sensitivity and specificity to the structural changes associated with progression of this disease. In the current study, we examined the relationship between radiographic JSW and MRI-derived articular cartilage thickness in subjects 4 years post anterior cruciate ligament reconstruction (ACLR) who were at increased risk for the onset and early progression of post-traumatic OA, and in uninjured subjects with normal knees (Control). In both ACLR and Control groups, there were large measurement biases, wide limits of agreement, and poor correlation between the two measurement techniques. Clinical significance: The finding from this study suggest that the two methods of examining changes associated with the onset and early progression of PTOA either characterize different structures about the knee and should not be used interchangeably, or two-dimensional JSW measurements are not sensitive to small changes in articular cartilage thickness.

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