Level of evidence and authorship trends of clinical studies in knee surgery, sports traumatology, arthroscopy, 1995-2015.

PURPOSE: There is increasing emphasis on publication quality and internationalization of author groups in orthopaedic literature. The purpose of this review was to evaluate the type of studies and the level of evidence (LOE) published in knee surgery, sports traumatology, arthroscopy (KSSTA) from 1995 to 2015. The secondary aim was to analyze trends in authorship characteristics in KSSTA. METHODS: Two reviewers reviewed the table of contents of KSSTA and identified original papers from 1995, 2000, 2005, 2010, and 2015. The reviewers graded LOE from Levels I to IV using guidelines from the University of Oxford's Centre for Evidence-Based Medicine. For each article, the total number of authors and country of author group were also analyzed. RESULTS: A total of 880 papers were analyzed. The proportions in LOE have stayed consistent throughout the study period (n.s.). There has been a significant increase in the number of published articles and the number of Level I and II studies (P < 0.01). Therapeutic articles were the most common type. The mean number of authors per KSSTA article significantly increased from 3.9 to 5.7 over the 20-year period (P < 0.01). The number of represented countries increased yearly and academic institutions from 40 different nationalities published articles in the Journal. Of the examined years, the percent of articles with international collaboration was 17.6%. CONCLUSION: The proportion of LOE I and II articles published in KSSTA remains consistently high. Therapeutic studies are the most frequently published articles. There is an increase in international groups publishing in KSSTA. LEVEL OF EVIDENCE: IV.

Ten Years of Sports Health: Authorship Characteristics and Levels of Evidence.

CONTEXT: Sports Health: A Multidisciplinary Approach, now 10 years into production, has been ranked a top-25 journal in sport sciences and has tripled its impact throughout its existence. OBJECTIVE: To evaluate authorship trends and levels of evidence (LOE) of articles published in Sports Health from 2009 to 2018. The secondary aim was to analyze funding sources and internationalization throughout the journal's tenure. DATA SOURCES: All clinical studies published in Sports Health between the years 2009 and 2018 were examined. STUDY SELECTION: All publications from the provided years were electronically reviewed by 2 reviewers and evaluated for inclusion criteria. Editorials, society news, memorials, letters to the editor, and corrigenda were excluded. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 5. DATA EXTRACTION: Articles were examined for number of authors, presence of female authorship, funding, country of origin, international collaboration, academic degree or certification of first and senior authors, and LOE. Clinical articles were assigned LOE based on guidelines from the University of Oxford's Centre for Evidence-Based Medicine. RESULTS: A total of 654 articles were examined. The percentage of high-LOE studies increased throughout the study period. The percentage of publications with female authors also increased throughout the study period. The mean number of authors per article increased from 3.2 to 4.6 over the 10-year period (P < 0.05). The percentage of publications with international collaboration stayed consistent, while the number of countries per year increased during the study period. Overall, institutions from 23 countries have published in Sports Health since its inception to the time of this study. CONCLUSION: Female authorship in Sports Health surpasses industry standards, and the percentage of high-LOE studies remains remarkably high. Sports Health has stayed true to its multidisciplinary scope, as evidenced by the authors' varying degrees and numerous countries that publish in the journal.

Optimization of the enhanced permeability and retention effect for near-infrared imaging of solid tumors with indocyanine green.

Surgery is the most effective method to cure patients with solid tumors. New techniques in near-infrared (NIR) cancer imaging are being used to identify surgical margins and residual tumor cells in the wound. Our goal was to determine the optimal time and dose for imaging solid tumors using Indocyanine Green. Syngeneic murine flank tumor models were used to test NIR imaging of ICG at various doses ranging from 0 to 10 mg/kg. Imaging was performed immediately after injection and up to 72 hours later. Biodistribution in the blood and murine organs were quantified by spectroscopy and fluorescence microscopy. Based on these results, a six patient dose titration study was performed. In murine flank tumors, the tumor-to-background ratio (TBR) for ICG at doses less than 5 mg/kg were less than 2 fold at all time points, and the surgeons could not subjectively identify tissue contrast. However, for doses ranging from 5 mg/kg to 10 mg/kg, the TBR ranged from 2.1 to 8.0. The tumor signal was best appreciated at 24 hours and the background was least pronounced after 24 hours. Biodistribution studies in the blood and murine organs revealed excretion through the biliary tree and gastrointestinal tract, with minimal blood fluorescence at the higher doses. A follow up pilot study confirmed that these findings were applicable to lung cancer patients, and tumor was clearly delineated from surrounding normal tissue by NIR imaging. For non-hepatic solid tumors, we found ICG was optimal when dosed at 5 mg/kg and 24 hours before surgery.

Small portable interchangeable imager of fluorescence for fluorescence guided surgery and research.

Fluorescence guided surgery (FGS) is a developing field of surgical and oncologic research. Practically, FGS has shown useful applications in urologic surgery, benign biliary surgery, colorectal cancer liver metastasis resection, and ovarian cancer debulking. Most notably in in cancer surgery, FGS allows for the clear delineation of cancerous tissue from benign tissue. FGS requires the utilization of a fluorescent contrast agent and an intraoperative fluorescence imaging device (IFID). Currently available IFIDs are expensive, unable to work with multiple fluorophores, and can be cumbersome. This study aims to describe the development and utility of a small, cost-efficient, and interchangeable IFID made from commercially available components. Extensive research was done to design and construct a light-weight, portable, and cost-effective IFID. We researched the capabilities, size, and cost of several camera types and eventually decided on a near-infrared (NIR) charged couple device (CCD) camera for its overall profile. The small portable interchangeable imager of fluorescence (SPIIF) is a "scout" IFID system for FGS. The main components of the SPIIF are a NIR CCD camera with an articulating light filter. These components and a LED light source with an attached heat sink are mounted on a small metal platform. The system is connected to a laptop by a USB 2.0 cable. Pixielink © software on the laptop runs the system by controlling exposure time, gain, and image capture. After developing the system, we evaluated its utility as an IFID. The system weighs less than two pounds and can cover a large area. Due to its small size, it is easily made sterile by covering it with any sterile plastic sheet. To determine the system's ability to detect fluorescent signal, we used the SPIIF to detect indocyanine green under ex and in-vivo conditions and fluorescein under ex-vivo conditions. We found the SPIIF was able to detect both ICG and fluorescein under different depths of a semi-opaque colloid. Second, we found that a concentration as low as 0.5 g/ml of indocyanine green dissolved in plasma was detectable. Lastly, in a murine and human cancer model, the SPIIF was able to detect indocyanine green signal within tumors and generate a signal-to-background ratio (SBR) of 3.75. This study shows that a low-cost IFID can be made from commercially available parts. Second, this IFID is capable of in and ex-vivo detection of multiple fluorophores without sacrificing its small size or favorable ergonomics.

Quantification of tumor fluorescence during intraoperative optical cancer imaging.

Intraoperative optical cancer imaging is an emerging technology in which surgeons employ fluorophores to visualize tumors, identify tumor-positive margins and lymph nodes containing metastases. This study compares instrumentation to measure tumor fluorescence. Three imaging systems (Spectropen, Glomax, Flocam) measured and quantified fluorescent signal-to-background ratios (SBR) in vitro, murine xenografts, tissue phantoms and clinically. Evaluation criteria included the detection of small changes in fluorescence, sensitivity of signal detection at increasing depths and practicality of use. In vitro, spectroscopy was superior in detecting incremental differences in fluorescence than luminescence and digital imaging (Ln[SBR] = 6.8 ± 0.6, 2.4 ± 0.3, 2.6 ± 0.1, p = 0.0001). In fluorescent tumor cells, digital imaging measured higher SBRs than luminescence (6.1 ± 0.2 vs. 4.3 ± 0.4, p = 0.001). Spectroscopy was more sensitive than luminometry and digital imaging in identifying murine tumor fluorescence (SBR = 41.7 ± 11.5, 5.1 ± 1.8, 4.1 ± 0.9, p = 0.0001), and more sensitive than digital imaging at detecting fluorescence at increasing depths (SBR = 7.0 ± 3.4 vs. 2.4 ± 0.5, p = 0.03). Lastly, digital imaging was the most practical and least time-consuming. All methods detected incremental differences in fluorescence. Spectroscopy was the most sensitive for small changes in fluorescence. Digital imaging was the most practical considering its wide field of view, background noise filtering capability, and sensitivity to increasing depth.

Intraoperative molecular imaging can identify lung adenocarcinomas during pulmonary resection.

BACKGROUND: More than 80,000 people undergo resection of a pulmonary tumor each year, and the only method to determine if the tumor is malignant is histologic analysis. We propose that a targeted molecular contrast agent could bind lung adenocarcinomas, which could be identified using real-time optical imaging at the time of surgery. METHODS: Fifty patients with a biopsy-proven lung adenocarcinoma were enrolled. Before surgery, patients were systemically administered 0.1 mg/kg of a fluorescent folate receptor alpha (FRα)-targeted molecular contrast agent by intravenous infusion. During surgery, tumors were imaged in situ and ex vivo, after the lung parenchyma was dissected to directly expose the tumor to the imaging system. RESULTS: Tumors ranged from 0.3 to 7.5 cm (mean: 2.6 cm), and 46 of 50 (92%) lung adenocarcinomas were fluorescent. No false uptake occurred, and in 2 cases, intraoperative imaging revealed tumor metastases (3 mm and 6 mm) that were not recognized preoperatively. Four adenocarcinomas were not fluorescent, and immunohistochemistry showed that these adenocarcinomas did not express FRα. Tumor fluorescence was independent of nodule size, uptake of 2-deoxy-2-((18)F)fluoro-D-glucose, histology, and tumor differentiation. Molecular imaging could identify only 7 of the 50 adenocarcinomas in situ in the patient without bisection. The most important predictor of the success of molecular imaging in locating the tumor in situ was the distance of the nodule from the pleural surface. CONCLUSIONS: Intraoperative molecular imaging with a targeted contrast agent can identify lung adenocarcinomas, and this technology is currently useful in patients with subpleural tumors, irrespective of size. With further refinements, this tool may prove useful in locating adenocarcinomas that are deeper in the lung parenchyma, in lymph nodes, and at pleural and resection margins.

Adenoviral-based immunotherapy provides local disease control in an orthotopic murine model of esophageal cancer.

Despite recent advances in the development of novel therapies, esophageal carcinoma remains an aggressive cancer associated with a poor prognosis. The lack of a high throughput, reproducible syngeneic animal model that replicates human disease is partly responsible for the paucity of novel therapeutic approaches. In this report, we present the first successful syngeneic, orthotopic model for esophageal cancer. This model was used to test an established adenoviral-based tumor vaccine. We utilized a murine esophageal cancer cell line established from the ED-L2-cyclin D1;p53 mouse that was transduced to express a viral tumor antigen, the Human Papilloma Virus (HPV) E7 protein. The tumor was established in its natural microenvironment at the gastroesophageal junction. Tumor growth was consistent and reproducible. An adenoviral vaccine to E7 (Ad.E7) induced an E7-specific population of functionally active CD8 T cells that trafficked into the tumors and retained cytotoxicity. Ad.E7 vaccination reduced local tumor growth and prolonged overall survival. These findings suggest that orthotopic tumor growth is a reasonable preclinical model to validate novel therapies.

Cognitive function, mental health, and health-related quality of life after lung transplantation.

RATIONALE: Cognitive and psychiatric impairments are threats to functional independence, general health, and quality of life. Evidence regarding these outcomes after lung transplantation is limited. OBJECTIVES: Determine the frequency of cognitive and psychiatric impairment after lung transplantation and identify potential factors associated with cognitive impairment after lung transplantation. METHODS: In a retrospective cohort study, we assessed cognitive function, mental health, and health-related quality of life using a validated battery of standardized tests in 42 subjects post-transplantation. The battery assessed cognition, depression, anxiety, resilience, and post-traumatic stress disorder (PTSD). Cognitive function was assessed using the Montreal Cognitive Assessment, a validated screening test with a range of 0 to 30. We hypothesized that cognitive function post-transplantation would be associated with type of transplant, cardiopulmonary bypass, primary graft dysfunction, allograft ischemic time, and physical therapy post-transplantation. We used multivariable linear regression to examine the relationship between candidate risk factors and cognitive function post-transplantation. MEASUREMENTS AND MAIN RESULTS: Mild cognitive impairment (score, 18-25) was observed in 67% of post-transplant subjects (95% confidence interval [CI]: 50-80%) and moderate cognitive impairment (score, 10-17) was observed in 5% (95% CI, 1-16%) of post-transplant subjects. Symptoms of moderate to severe anxiety and depression were observed in 21 and 3% of post-transplant subjects, respectively. No transplant recipients reported symptoms of PTSD. Higher resilience correlated with less psychological distress in the domains of depression (P < 0.001) and PTSD (P = 0.02). Prolonged graft ischemic time was independently associated with worse cognitive performance after lung transplantation (P = 0.001). The functional gain in 6-minute-walk distance achieved at the end of post-transplant physical rehabilitation (P = 0.04) was independently associated with improved cognitive performance post-transplantation. CONCLUSIONS: Mild cognitive impairment was present in the majority of patients after lung transplantation. Prolonged allograft ischemic time may be associated with cognitive impairment. Poor physical performance and cognitive impairment are linked, and physical rehabilitation post-transplant and psychological resilience may be protective against the development of long-term impairment. Further study is warranted to confirm these potential associations and to examine the trajectory of cognitive function after lung transplantation.