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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.

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.

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 β-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 β-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis. Circulating tumour cells contribute to metastatic spread. Here the authors find that beta-chain of haemoglobin is overexpressed in those cells and protects them from oxidative stress, prolonging their survival in circulation and thereby increasing the likelihood of metastasis formation.

Baseball is unique in its multiple facets: pitching, hitting, base rounding, and fielding are distinct activities that require different athletic skills to perform at a high level. Likewise, these different aspects of the game can contribute to a multitude of varying injuries. While high-velocity overhead throwing, along with batting, can produce a plethora of upper extremity injuries that often garner attention, injuries to the lower extremity can severely impact a player’s performance and ability to compete. The rigors of the short, explosive sprinting required for base running, as well as the dynamic movement required for fielding, create ample opportunity for lower limb injury, and even subtle pathology can affect a pitcher’s ability to perform or increase their long-term risk of injury. Chronic injury from conditions such as femoroacetabular impingement and hip labral tears can also occur. The purpose of the present review is to summarize the relevant epidemiology, pathophysiology, and treatment of lower extremity injuries in baseball athletes, with reference to current research into the prevention and management of such injuries.

While physicians advise patients on healthy lifestyle habits, physicians may struggle to abide by their own recommendations. We sought to characterize resident physician participation in exercise, their barriers to exercise, and the effect of exercise on their overall wellness. We hypothesized that residents who exercised would have less depression and greater wellbeing. Trainees at a university-based institution were surveyed. Data regarding exercise habits, hours worked, barriers to exercise, and mental health were acquired. Mental health was assessed via the Patient Health Questionnaire-2. Inter-group differences were analyzed using chi-squared testing; statistical significance was set at P<0.05. 129 trainees responded to the survey. 84 trainees reported exercising while 45 denied. 63 exercisers reported “living a healthy lifestyle” compared to 18 nonexercisers (P<0.001). Exercisers were more likely to report “Time” as their greatest barrier to exercise (P<0.001). Fifty-five exercisers answered “Not at all” when asked about how often they experience anhedonia compared to 23 non-exercisers. Trainees who exercise are more likely to report living a healthy lifestyle and less likely to experience anhedonia than non-exercisers, demonstrating the importance of exercise during residency.

Background: Meniscal extrusion refers to meniscal displacement out of the joint space and over the tibial margin, altering knee mechanics and increasing the risk of osteoarthritis. The meniscotibial ligaments have been shown to have an important role in meniscal stability. However, it remains unclear whether an isolated lesion of the medial meniscotibial ligaments will result in meniscal extrusion and whether repairing the detached ligament will reduce extrusion. Hypothesis: A lesion of the medial meniscotibial ligament will result in meniscal extrusion, and repairing the joint capsule will eliminate the extrusion by returning the meniscus back to its original position. Study Design: Controlled laboratory study. Methods: Fresh-frozen human cadaveric knees (N = 6) were used for biomechanical testing. The test protocol involved 100 flexion-extension cycles. In full extension, meniscal extrusion was measured using ultrasound, in both an otherwise unloaded state and while subjected to a 10-N·m varus load. Each knee was tested in its native condition (baseline), after creating a detachment of the medial meniscotibial ligament, and finally with the joint capsule repaired using 3 knotless SutureTak anchors. We also performed a retrospective review of 15 patients who underwent meniscotibial ligament repair with a minimal follow-up of 5 weeks (mean, 14 weeks; range, 5-35 weeks). Results: During biomechanical testing, the mean absolute meniscal extrusion at baseline was 1.5 ± 0.6 mm. After creation of the meniscotibial ligament lesion, the mean absolute meniscal extrusion was significantly increased (3.4 ± 0.7 mm) (P < .001). After repair, the extrusion was reduced to 2.1 ± 0.4 mm (P < .001). Clinically, a reduction in absolute meniscal extrusion of approximately 48% was reached (1.2 ± 0.6 vs 2.4 ± 0.5 mm preoperatively; P < .001). Conclusion: This study indicates that the medial meniscotibial ligaments contribute to meniscal stability as lesions cause the meniscus to extrude and that repair of those ligaments can significantly reduce extrusion. Early clinical results using this meniscotibial ligament repair technique support our biomechanical findings, as a significant reduction in meniscal extrusion was achieved. Clinical Relevance: Our biomechanical findings suggest that repair of medial meniscotibial ligaments reduces meniscal extrusion and clinically may improve meniscal function, with the possible long-term benefit of reducing the risk for osteoarthritis.

Child abuse is common in the United States but is often undetected. The incidence of this form of abuse is difficult to quantify, but children with a history of abuse are at risk of chronic health conditions. Medical providers are in the unique position of triaging trauma patients and differentiating unintentional from abusive trauma, as well as having the important position of being a mandated reporter of abuse in all states. Obtaining a detailed history and screening for risk factors can help identify children at risk of abuse. Certain orthopedic injuries may be related to abuse, which may trigger clinical suspicion and lead to further workup or intervention. By increasing awareness, through medical provider education and increased screening, earlier detection of abuse may prevent more serious injuries and consequences. This review evaluates current literature regarding the orthopedic manifestations of child abuse in hopes of increasing medical provider awareness.ImpactChild abuse is common in the United States but often remains undetected.Medical professionals are in the unique position of evaluating trauma patients and identifying concerns for abusive injuries.Certain orthopedic injuries may raise concern for abuse triggering clinical suspicion and further workup or intervention.

Background: Patient resilience and mental health, including anxiety and depression, are increasingly recognized as critical factors influencing outcomes in orthopaedic surgery. However, the relative effect of these psychosocial factors on postoperative outcomes after hip arthroscopy remains unclear. Purpose: To quantify the relationship between anxiety, depression, the Brief Resilience Scale (BRS), and 4 validated patient-reported outcomes (PROMs) after hip arthroscopy. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of prospectively collected data for patients undergoing primary hip labrum repair from January 1, 2021, to January 1, 2022. Patients completed the BRS and 4 PROMs—modified Harris Hip Score (mHHS), visual analog scale for pain (VAS), Hip Outcomes Score for Activities of Daily Living (HOS-ADL), and Hip Outcomes Score for Sports-Related Activities (HOS-SP)—preoperatively, 6 months, 1 year, and 2 years postoperatively. Patients were stratified into tertiles based on baseline BRS scores: low resilience, normal resilience, and high resilience. Outcomes were analyzed using t tests, 1-way analysis of variance, principal component analysis, and Pearson correlation coefficients to assess relationships between resilience, anxiety, depression, and PROMs. Results: In total, 35 patients met the inclusion criteria with a mean follow-up of 741.4 days. Resilience showed a variable effect on PROMs, with no consistent differences observed across resilience tertiles at any follow-up interval. In contrast, patients with a history of anxiety and/or depression had significantly lower mHHS scores (68.7 vs 80.5, P = .041) and higher VAS scores (8.7 vs 3.9, P = .017) at 2 years, compared with those without such a history. Principal component analysis further highlighted the stronger association of anxiety and depression with outcomes compared with resilience at 6 months (P = .041), 1 year (P = .026), and the 2-year follow-up (P = .014). Overall, 85.7% of patients achieved the minimal clinically important difference for mHHS, 85.7% for VAS, 65.7% for HOS-ADL, and 67.5% for HOS-SP. Conclusion: The present study suggests that a history of anxiety and/or depression is consistently associated with poorer outcomes after arthroscopic hip surgery, whereas resilience demonstrates a less consistent and variable association.

Background: Concussions have received national attention in collision sports such as football, soccer, and hockey, but less focus has been placed on basketball. Purpose: To determine return-to-play (RTP) and player performance in the first and second season after concussion in National Basketball Association (NBA) players. Study Design: Descriptive epidemiology study. Methods: An online database of publicly available NBA athlete injuries was queried for instances of “concussion” between 2010 and 2018. The age at injury, team, position, height, weight, body mass index, NBA experience, date of concussion, date of return, and seasons played postconcussion was recorded for each player. Regular-season statistics (games started, games played, minutes played, and player efficiency rating [PER]) were compiled for the season before, and 2 seasons immediately after, injury. Kaplan-Meier survivorship plots were computed for athlete RTP and retirement endpoints. Results: A total of 81 injuries were identified from 2010 to 2018, with a rate of 2.0 concussions per 100 player-years. Overall RTP was 100% after concussion, with nearly all (88%) returning in the season of injury; 12% of players experienced a season-ending concussion. RTP averaged 37.3 days after injury, varying widely (range, 2-291 days). Compared with preinjury season (78.0%), athletes played in significantly fewer overall games in the season of injury (36.6%; P < .0001), as well as 1 (69.5%; P = .0229) and 2 seasons postinjury (73.2%; P = .3192). PER scores were not significantly different across the study period. Each point increase in a player’s preinjury PER score was associated with a 2.4% decrease in PER from the preinjury season to season of injury (P = .0016) and a 3.1% decrease from preinjury to season after injury (P = .0053). Each increasing year of age or year of experience was associated with 5% decline in PER score at 1 season after injury. Conclusion: NBA players had a high RTP after concussion, with most returning in the same season as the injury. Players sustaining concussions played significantly fewer games for at least 2 seasons after injury. Performance via PER did not change across the entire cohort; however, players with higher preinjury PER, and older players were more likely to sustain a greater decline in performance after injury.