Defining the contemporary epidemiology and return to play for high ankle sprains in the National Football League.

BACKGROUND: High ankle sprains and syndesmotic injuries are commonly sustained by National Football League players, yet there is apaucity of literature reporting the incidence, risk factors and return to play (RTP) rates for these injuries. The purpose of this study is to examine the epidemiology and trends in incidence of high ankle sprains across 11 NFL seasons. METHODS: Publicly available data from the 2009-2010 through 2019-20 seasons were reviewed to identify injuries and collect player characteristics and return to play. Incidence of high ankle injuries was calculated per 10,000 athlete-exposures. Linear regression was performed for incidence of injuries. Risk factors for failure to RTP were identified through multivariate logistic regression, controlling foryear of injury, player position, body mass index (BMI), age at injury, and years of experience before injury. RESULTS: A total of 533 high ankle sprains were identified in 498 players at an average age of 25.8 ± 3.1 and average BMI of 31.8 ± 4.6. The annual incidence of high ankle sprains in the NFL increased at alinear rate of 0.067per 10,000 player exposures (R2 = 0.3357) in 2009, to 1.75per 10,000 player exposures to 2.49 in 2019-20. Most injuries were in offensive players (304/533 injuries, 57.0%). Overall, 89.7% (478/533) of players returned to play; average RTP time was 80.5 ± 132.9 days. Defensive players had afaster RTP (68.1 ± 114.6 days) compared to offensive players (90.1 ± 144.8 days) (p = 0.084). Higher age at injury was found to increase the risk of failure to RTP (p = 0.0088). CONCLUSION: RTP rate was high following high ankle sprain aamongNFL players at 90%, with an average recovery period of 11 weeks. Defensive players experience RTP faster than offensive players. Future studies are needed to determine performance outcomes following RTP, along with which patients might benefit from surgery.

Malpractice Litigation Involving Chiropractic Spinal Manipulation.

OBJECTIVE: To evaluate the relationship between chiropractic spinal manipulation and medical malpractice using a legal database. METHODS: The legal database VerdictSearch was queried using the terms "chiropractor" OR "spinal manipulation" under the classification of "Medical Malpractice" between 1988 and 2018. Cases with chiropractors as defendants were identified. Relevant medicolegal characteristics were obtained, including legal outcome (plaintiff/defense verdict, settlement), payment amount, nature of plaintiff claim, and type and location of alleged injury. RESULTS: Forty-eight cases involving chiropractic management in the United States were reported. Of these, 93.8% (n = 45) featured allegations involving spinal manipulation. The defense (practitioner) was victorious in 70.8% (n = 34) of cases, with a plaintiff (patient) victory in 20.8% (n = 10) (mean payment $658,487 ± $697,045) and settlement in 8.3% (n = 4) (mean payment $596,667 ± $402,534). Overaggressive manipulation was the most frequent allegation (33.3%; 16 cases). A majority of cases alleged neurological injury of the spine as the reason for litigation (66.7%, 32 cases) with 87.5% (28/32) requiring surgery. C5-C6 disc herniation was the most frequently alleged injury (32.4%, 11/34, 83.3% requiring surgery) followed by C6-C7 herniation (26.5%, 9/34, 88.9% requiring surgery). Claims also alleged 7 cases of stroke (14.6%) and 2 rib fractures (4.2%) from manipulation therapy. CONCLUSIONS: Litigation claims following chiropractic care predominately alleged neurological injury with consequent surgical management. Plaintiffs primarily alleged overaggressive treatment, though a majority of trials ended in defensive verdicts. Ongoing analysis of malpractice provides a unique lens through which to view this complicated topic.

Internet accuracy of publicly available images of meniscal tears.

BACKGROUND: The Internet is an easily accessible resource for both providers and patients. Despite this, the Internet is not peer reviewed, leaving Internet searches subject to inaccuracies, especially with regards to medical information. The purpose of this study was to review Internet images of meniscus tears using three popular search engines: Google, Bing, and Yahoo. METHODS: A search query was performed on the aforementioned search engines for the term: 'meniscus tear'. The first 100 images found for each individual search were analyzed by two independent reviewers with different levels of orthopedic training (orthopedic surgery resident and medical student). Inter-rate reliability and accuracy was determined for each of the search engines. The images were defined based on the source that published the image as either educational (published by hospital or medical association), commercial (published by a device company), or individual (published via a physician). RESULTS: The inter-rater reliability was excellent (Cronbach's alpha = 0.91), (Cronbach's alpha = 0.94), (Cronbach's alpha >0.90) on Google, Bing, and Yahoo, respectively. When comparing the search engines for correctness, Google had 82% accuracy, compared to 81% for Bing and Yahoo. All three search engines have a similar mix of source material with educational images consisting of 86% of Google images, 84% for Yahoo, and 89% for Bing. CONCLUSION: Our study revealed that the three search engines queried displayed meniscal tear images with >80% accuracy when evaluated by two independent reviewers. Despite this, many images may still be seen as highly technical, or esoteric to an untrained individual. Ultimately, physicians should take an active role in making high quality, easy to understand medical resources, and anatomic diagrams available to their patients to avoid confusion and enhance understanding.

Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy.

A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.

An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTCM score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288-303. ©2018 AACR.See related commentary by Heitzer and Speicher, p. 269This article is highlighted in the In This Issue feature, p. 253.

Expression of ß-globin by cancer cells promotes cell survival during blood-borne dissemination.

Metastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, but their survival mechanisms are not well defined. Here, comparing single-cell RNA-Seq profiles of CTCs from breast, prostate and lung cancers, we observe consistent induction of ß-globin (HBB), but not its partner α-globin (HBA). The tumour-specific origin of HBB is confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggers HBB induction, mediated through the transcriptional regulator KLF4. Depletion of HBB in CTC-derived cultures has minimal effects on primary tumour growth, but it greatly increases apoptosis following ROS exposure, and dramatically reduces CTC-derived lung metastases. These effects are reversed by the anti-oxidant N-Acetyl Cysteine. Conversely, overexpression of HBB is sufficient to suppress intracellular ROS within CTCs. Altogether, these observations suggest that ß-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.

An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma.

Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent.

Spinal Cord Inflammation: Molecular Imaging after Thoracic Aortic Ischemia Reperfusion Injury.

Purpose To evaluate whether noninvasive molecular imaging technologies targeting myeloperoxidase (MPO) can reveal early inflammation associated with spinal cord injury after thoracic aortic ischemia-reperfusion (TAR) in mice. Materials and Methods The study was approved by the institutional animal care and use committee. C57BL6 mice that were 8-10 weeks old underwent TAR (n = 55) or sham (n = 26) surgery. Magnetic resonance (MR) imaging (n = 6) or single photon emission computed tomography (SPECT)/computed tomography (CT) (n = 15) studies targeting MPO activity were performed after intravenous injection of MPO sensors (bis-5-hydroxytryptamide-tetraazacyclododecane [HT]-diethyneletriaminepentaacetic acid [DTPA]-gadolinium or indium 111-bis-5-HT-DTPA, respectively). Immunohistochemistry and flow cytometry were used to identify myeloid cells and neuronal loss. Proinflammatory cytokines, keratinocyte chemoattractant (KC), and interleukin 6 (IL-6) were measured with enzyme-linked immunosorbent assay. Statistical analyses were performed by using nonparametric tests and the Pearson correlation coefficient. P < .05 was considered to indicate a significant difference. Results Myeloid cells infiltrated into the injured cord at 6 and 24 hours after TAR. MR imaging confirmed the presence of ischemic lesions associated with mild MPO-mediated enhancement in the thoracolumbar spine at 24 hours compared with the sham procedure. SPECT/CT imaging of MPO activity showed marked MPO-sensor retention at 6 hours (P = .003) that continued to increase at 24 hours after TAR (P = .0001). The number of motor neurons decreased substantially at 24 hours after TAR (P < .01), which correlated inversely with in vivo inflammatory changes detected at molecular imaging (r = 0.64, P = .0099). MPO was primarily secreted by neutrophils, followed by lymphocyte antigen 6 complexhigh monocytes and/or macrophages. There were corresponding increased levels of proinflammatory cytokines KC (P = .0001) and IL-6 (P = .0001) that mirrored changes in MPO activity. Conclusion MPO is a suitable imaging biomarker for identifying and tracking inflammatory damage in the spinal cord after TAR in a mouse model. © RSNA, 2016 Online supplemental material is available for this article.

Effect of limb demand ischemia on autophagy and morphology in mice.

BACKGROUND: Obesity is a major risk factor for diabetes and peripheral arterial disease, which frequently leads to lower limb demand ischemia. Skeletal muscle autophagy and mitochondrial biogenesis are important processes for proper oxidative capacity and energy metabolism, which are compromised in diabetes. This study compares autophagy, mitochondrial biogenesis, energy metabolism, and morphology in the hind limbs of obese diabetic mice subjected to demand or sedentary ischemia. MATERIALS AND METHODS: Unilateral hind limb demand ischemia was created in a group of diet-induced obese mice after femoral artery ligation and 4 wk of daily exercise. A parallel group of mice underwent femoral artery ligation but remained sedentary for 4 wk. Hind limb muscles were analyzed for markers of autophagy, mitochondrial biogenesis, adenosine triphosphate, and muscle tissue morphology. RESULTS: At the end of the 4-wk exercise period, demand ischemia increased the autophagy mediator Beclin-1, but it did not alter the autophagy indicator, LC3B-II/I ratio, or markers of mitochondrial biogenesis, optic atrophy/dynamin-related protein. In contrast, exercise significantly increased the level of mitochondrial protein-succinate dehydrogenase subunit-A and reduced adipocyte accumulation and the percentage of centrally nucleated myofibers in the demand ischemia limb. In addition, demand ischemia resulted in decreased uncoupling protein-3 levels without altering muscle adenosine triphosphate or pS473-Akt levels. CONCLUSIONS: Limb demand ischemia markedly decreased adipocyte accumulation and enhanced muscle regeneration in obese mice, but it did not appear to enhance autophagy, mitochondrial biogenesis, energy metabolism, or insulin sensitivity. Future studies aimed at evaluating novel therapies that enhance autophagy and mitochondrial biogenesis in diabetes with peripheral arterial disease are warranted.