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Strontium-90 is a radionuclide found in high concentrations in nuclear reactor waste and nuclear fallout from reactor accidents and atomic bomb explosions. In the 1950s, little was known regarding the health consequences of strontium-90 internalization. To assess the health effects of strontium-90 ingestion in infancy through adolescence, the Atomic Energy Commission and Department of Energy funded large-scale beagle studies at the University of California Davis. Conducted from 1956 to 1989, the strontium-90 ingestion study followed roughly 460 beagles throughout their lifespans after they were exposed to strontium-90 in utero (through feeding of the mother) and fed strontium-90 feed at varying doses from weaning to age 540 days. The extensive medical data and formalin-fixed paraffin-embedded tissues were transferred from UC Davis to the National Radiobiology Archive in 1992 and subsequently to the Northwestern University Radiobiology Archive in 2010. Here, we summarize the design of the strontium-90 ingestion study and give an overview of its most frequent recorded findings. As shown before, radiation-associated neoplasias (osteosarcoma, myeloproliferative syndrome and select squamous cell carcinomas) were almost exclusively observed in the highest dose groups, while the incidence of neoplasias most frequent in controls decreased as dose increased. The occurrence of congestive heart failure in each dose group, not previously assessed by UC Davis researchers, showed a non-significant increase between the controls and lower dose groups that may have been significant had sample sizes been larger. Detailed secondary analyses of these data and samples may uncover health endpoints that were not evaluated by the team that conducted the study., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Objective: The mini-open lateral retropleural (MO-LRP) approach is an effective option for surgically treating thoracic disc herniations, but the approach raises concerns for pneumothorax (PTX). However, chest tube placement causes insertion site tenderness, necessitates consultation services, increases radiation exposure (requires multiple radiographs), delays the progression of care, and increases narcotic requirements. This study examined the incidence of radiographic and clinically significant PTX and hemothorax (HTX) after the MO-LRP approach, without the placement of a prophylactic chest tube, for thoracic disc herniation., Methods: This study was a single-institution retrospective evaluation of consecutive cases from 2017 to 2022. Electronic medical records were reviewed, including postoperative chest radiographs, radiology and operative reports, and postoperative notes. The presence of PTX or HTX was determined on chest radiographs obtained in all patients immediately after surgery, with interval radiographs if either was present. The size was categorized as large (≥ 3 cm) or small (< 3 cm) based on guidelines of the American College of Chest Physicians. PTX or HTX was considered clinically significant if it required intervention., Results: Thirty patients underwent thoracic discectomy via the MO-LRP approach. All patients were included. Twenty patients were men (67%), and 10 (33%) were women. The patients ranged in age from 25 to 74 years. The most commonly treated level was T11-12 (n = 11, 37%). Intraoperative violation of parietal pleura occurred in 5 patients (17%). No patient had prophylactic chest tube placement. Fifteen patients (50%) had PTX on postoperative chest radiographs; 2 patients had large PTXs, and 13 had small PTXs. Both patients with large PTXs had expansion on repeat radiographs and were treated with chest tube insertion. Of the 13 patients with a small PTX, 1 required 100% oxygen using a nonrebreather mask; the remainder were asymptomatic. One patient, who had no abnormal findings on the immediate postoperative chest radiograph, developed an incidental HTX on postoperative day 6 and was treated with chest tube insertion. Thus, 3 patients (10%) required a chest tube: 2 for expanding PTX and 1 for delayed HTX., Conclusions: Most patients who undergo thoracic discectomy via the MO-LRP approach do not develop clinically significant PTX or HTX. PTX and HTX in this patient population should be treated with a chest tube only when there are postoperative clinical and radiographic indications.

Background and Objectives: Degenerative lumbar spondylolisthesis is associated with significant pain and disability. The literature on the treatment options and clinical outcomes for lumbar anterolisthesis is robust, but very few reports specifically evaluate lumbar retrolisthesis. This study investigated surgical outcomes for symptomatic L5-S1 retrolisthesis treated with stand-alone L5-S1 anterior lumbar interbody fusion (ALIF)., Methods: All patients with symptomatic L5-S1 retrolisthesis treated with stand-alone L5-S1 ALIF at a single institution over a 7-year period were identified. Exhaustive nonoperative management had failed for all patients. Patients with previous lumbar fusion were excluded. Preoperative and postoperative radiographic images and patient-reported outcome measures for 20 patients (14 males and 6 females; mean [SD] age, 50.3 [13.7] years) were analyzed., Results: The mean (SD) follow-up was 43.0 (23.7) months (range, 12.1-102.5 months). Patients experienced postoperative improvements in L5-S1 retrolisthesis (P = .048), L5-S1 disk height and angle (P < .001), L5 foraminal height (P < .001), L5-S1 lordosis (P < .001), and lumbar lordosis (P = .01). There were no significant changes in spinopelvic parameters. At the most recent follow-up, minimal clinically important differences in Oswestry Disability Index score, 36-Item Short-Form Survey (SF-36), and numerical rating scale score for leg pain were achieved in 11 of 20 (55%), 7 of 14 (50%), and 7 of 13 (54%) patients, respectively. All patients demonstrated fusion with no graft subsidence at up to 32 months. No patient experienced intraoperative complications, was readmitted, or required a subsequent posterior decompression or fusion because of refractory symptoms., Conclusion: In our cohort, stand-alone L5-S1 ALIF was associated with radiographic and clinical improvement in patients with symptomatic L5-S1 retrolisthesis., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Introduction: Traumatic brain injury (TBI) results in the death of over 50,000 and the permanent disability of 80,000 individuals annually in the United States. Much of the permanent disability is the result of secondary brain injury from intracranial hypertension (ICH). Pentobarbital coma is often instituted following the failure of osmotic interventions and sedation to control intracranial pressure (ICP). The goal of this study was to evaluate the efficacy of pentobarbital coma with respect to ICP management and long-term functional outcome., Methods: Traumatic brain injury patients who underwent pentobarbital coma at a level 1 trauma center between 2014 and 2021 were identified. Patient demographics, injury characteristics, Glasgow Coma Scale (GCS) scores, intracranial pressures (ICPs), and outcomes were obtained from the trauma registry as well as inpatient and outpatient medical records. The proportion of ICPs below 20 for each hospitalized patient-day was calculated. The primary outcome measured was GCS score at the last follow-up visit., Results: 25 patients were identified, and the majority were male (n ​= ​23, 92%) with an average age of 30.0 years ​± ​12.9 and median injury severity score of 30 (21.5-33.5). ICPs were monitored for all patients with a median of 464 (326-1034) measurements. The average hospital stay was 16.9 days ​± ​11.5 and intensive care stay was 16.9 ​± ​10.8 days. 9 (36.0%) patients survived to hospital discharge. Mean follow-up time in months was 36.9 ​± ​28.0 (min-max 3-80). 7 of the 9 surviving patients presented as GCS 15 on follow-up and the remaining were both GCS 9. Patients presenting at last follow-up with GCS 15 had a significantly higher proportion of controlled ICPs throughout their hospitalization compared to patients who expired or with follow-up GCS <15 (GCS 15: 88% ​± ​10% vs. GCS <15 or dead: 68% ​± ​22%, P ​= ​0.006). A comparison of the daily proportion of controlled ICPs by group revealed negligible differences prior to pentobarbital initiation. Groups diverged nearly immediately upon pentobarbital coma initiation with a higher proportion of controlled ICPs for patients with follow-up GCS of 15., Conclusion: Patients that do not have an immediate response to pentobarbital coma therapy for ICH universally had poor outcomes. Alternative therapy or earlier palliation should be considered for such patients. In contrast, patients whose ICPs responded quickly to pentobarbital had excellent long-term outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Thoracic disk herniations are challenging to treat, and open transthoracic or minimally invasive thoracoscopic approaches are associated with significant morbidity, substantial costs, and steep learning curves. The minimally invasive lateral retropleural thoracic diskectomy (MIS-LRP-TD) approach is straightforward and is associated with lower perioperative morbidity. With MIS-LRP-TD, the overlying rib, ipsilateral pedicle, ligamentum flavum, posterior longitudinal ligament, and posterior third of the adjacent vertebral bodies are resected. Adjunct fixation is typically not performed, eliminating hardware-related complications and costs. This radiographic study investigates long-term global and thoracic spine alignment after MIS-LRP-TD without fixation., Methods: This study was a single-institution, retrospective evaluation of all patients who underwent MIS-LRP-TD without fixation between November 7, 2017 and July 19, 2022. Preoperative and the most recent postoperative radiographs were used to determine the C7 plumb line to central sacral vertical line, thoracic Cobb angle (TCA), segmental Cobb angle, C7 to sagittal vertical axis, thoracic kyphosis, and segmental kyphosis., Results: In total, 22 patients with 24 disk herniations underwent MIS-LRP-TD without fixation. The mean (SD) radiographic follow-up was 12.9 (11.2) months. Overall, no significant differences were seen in C7 plumb line to central sacral vertical line (P = .65), C7 to sagittal vertical axis (P = .99), thoracic kyphosis (P = .30), TCA (P = .28), segmental kyphosis (P = .27), or segmental Cobb angle (P = .56) at follow-up. One patient demonstrated a >5° change in TCA but remained asymptomatic., Conclusion: Despite requiring extensive resection of the middle column and ipsilateral costovertebral joint at the index level, MIS-LRP-TD without adjunct fixation does not lead to significant global, regional, or segmental deformity. Thus, MIS-LRP-TD appears to be a safe, effective treatment approach for challenging thoracic disk herniations., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Objective: Industry partnerships help advance the field of neurosurgery. Given the nature of the field and its close relationship with innovation, neurosurgeons frequently partner with the medical device industry to advance technology and improve outcomes. However, this can create important ethical concerns for patients. In this paper, the authors sought to comprehensively study how physician payments from medical device companies have changed and what geographic parameters influence the trends observed over the years., Methods: The authors queried and merged several large databases, including Medicare and Medicaid provider usage data and databases from the Open Payments Program, National Plan and Provider Enumeration System, and US Census Bureau. Geospatial analysis was performed using Moran's I and II clustering. Univariate and multivariable analyses were performed using the Mann-Whitney U-test and geospatially weighted multivariable regression for hot spot and cold spot membership., Results: Data for 952 counties across the continental United States were analyzed. Ninety-seven counties constituted geographic hot spots. These hot spots were primarily concentrated in Florida, the New York-Pennsylvania region, central Colorado, and southwestern United States. Independent predictors of hot spot membership included greater unemployment rates, the percentage of White patients, the presence of mobile homes, and the percentage of county Hispanic and Black populations. Company-based differences were examined. The vast majority of Medtronic's payments were in the form of royalties and licensing (86.6%). Royalties and licensing accounted for the majority of payments for DePuy (69.4%), Globus Medical (62%), and NuVasive (77.1%). In contrast, other companies, such as Boston Scientific, opted to pay physicians in the form of ownership and investment interests (42.1%). The impact of the COVID-19 pandemic was also assessed. During the onset of the pandemic in 2020, physician payments fell or remained the same across all regions with the exception of the South Atlantic region. However, it was observed that nearly all regions rebounded, with stark elevations in physician payments immediately in 2021., Conclusions: This analysis demonstrates that there are national hot spots and cold spots of physician payments, and offers some social, economic, and company-dependent predictors that may influence the magnitude of payments. Further analysis is needed to better understand this clinical-commercial partnership in healthcare, specifically within neurosurgical practice.

Objective: Lateral lumbar interbody fusion (LLIF) is a workhorse surgical approach for lumbar arthrodesis. There is growing interest in techniques for performing single-position surgery in which LLIF and pedicle screw fixation are performed with the patient in the prone position. Most studies of prone LLIF are of poor quality and without long-term follow-up; therefore, the complication profile related to this novel approach is not well known. The objective of this study was to perform a systematic review and pooled analysis to understand the safety profile of prone LLIF., Methods: A systematic review of the literature and a pooled analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies reporting prone LLIF were assessed for inclusion. Studies not reporting complication rates were excluded., Results: Ten studies meeting the inclusion criteria were analyzed. Overall, 286 patients were treated with prone LLIF across these studies, and a mean (SD) of 1.3 (0.2) levels per patient were treated. The 18 intraoperative complications reported included cage subsidence (3.8% [3/78]), anterior longitudinal ligament rupture (2.3% [5/215]), cage repositioning (2.1% [2/95]), segmental artery injury (2.0% [5/244]), aborted prone interbody placement (0.8% [2/244]), and durotomy (0.6% [1/156]). No major vascular or peritoneal injuries were reported. Sixty-eight postoperative complications occurred, including hip flexor weakness (17.8% [21/118]), thigh and groin sensory symptoms (13.3% [31/233]), revision surgery (3.8% [3/78]), wound infection (1.9% [3/156]), psoas hematoma (1.3% [2/156]), and motor neural injury (1.2% [2/166])., Conclusions: Single-position LLIF in the prone position appears to be a safe surgical approach with a low complication profile. Longer-term follow-up and prospective studies are needed to better characterize the long-term complication rates related to this approach.

Honey bee abdominal lipids decline with age, a change thought to be associated with the onset of foraging behavior. Stressors, such as pesticides, may accelerate this decline by mobilizing internal lipid to facilitate the stress response. Whether bees with stressor-induced accelerated lipid loss vary from controls in both the onset of foraging and nutritional quality of collected pollen is not fully understood. We asked whether stressors affect foraging behavior through the depletion of abdominal lipid, and whether stress-induced lipid depletion causes bees to forage earlier and for fattier pollen. We tested this by treating newly emerged bees with one of two pesticides, pyriproxyfen (a juvenile hormone analog) and spirodiclofen (a fatty acid synthesis disruptor), that may affect energy homeostasis in non-target insects. Bees fed these pesticides were returned to hives to observe the onset of foraging behavior. We also sampled foraging bees to assay both abdominal lipids and dietary lipid content of their corbicular pollen. Initially, spirodiclofen-treated bees had significantly more abdominal lipids, but these declined faster compared with controls. These bees also collected less, yet more lipid-rich, pollen. Our results suggest that bees with accelerated lipid decline rely on dietary lipid content and must collect fattier pollen to compensate. Pyriproxyfen treatment reduced the age at first forage but did not affect abdominal or collected pollen lipid levels, suggesting that accelerated fat body depletion is not a prerequisite for precocious foraging., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Patients with prostate cancer whose tumors bear deleterious mutations in DNA-repair pathways often respond to PARP inhibitors. Studies were conducted to compare the activity of several PARP inhibitors in vitro and their tissue exposure and in vivo efficacy in mice bearing PC-3M-luc-C6 prostate tumors grown subcutaneously or in bone. Niraparib, olaparib, rucaparib, and talazoparib were compared in proliferation assays, using several prostate tumor cell lines and in a cell-free PARP-trapping assay. PC-3M-luc-C6 cells were approximately 12- to 20-fold more sensitive to PARP inhibition than other prostate tumor lines, suggesting that these cells bear a DNA damage repair defect. The tissue exposure and efficacy of these PARP inhibitors were evaluated in vivo in PC-3M-luc-C6 subcutaneous and bone metastasis tumor models. A steady-state pharmacokinetic study in PC-3M-luc-C6 tumor-bearing mice showed that all of the PARP inhibitors had favorable subcutaneous tumor exposure, but niraparib was differentiated by superior bone marrow exposure compared with the other drugs. In a PC-3M-luc-C6 subcutaneous tumor efficacy study, niraparib, olaparib, and talazoparib inhibited tumor growth and increased survival to a similar degree. In contrast, in the PC-3M-luc-C6 bone metastasis model, niraparib showed the most potent inhibition of bone tumor growth compared with the other therapies (67% vs. 40%-45% on day 17), and the best survival improvement over vehicle control [hazard ratio (HR), 0.28 vs. HR, 0.46-0.59] and over other therapies (HR, 1.68-2.16). These results show that niraparib has superior bone marrow exposure and greater inhibition of tumor growth in bone, compared with olaparib, rucaparib, and talazoparib., (©2022 American Association for Cancer Research.)

The lateral retropleural approach provides an eloquent, mini-open, safe corridor to address various pathologies in the thoracolumbar spine, including herniated thoracic discs. Traditional approaches (e.g., transpedicular, costotransversectomy, or transthoracic) have their own benefits and pitfalls but are generally associated with significant morbidity and often require instrumentation. In this video, the authors highlight the retropleural approach and its nuances, including patient positioning, surgical planning, relevant anatomy, surgical technique, and postoperative care. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2217., Competing Interests: Disclosures Dr. Uribe serves as a consultant for Mainstay Medical, Viseon, Misonix, SI Bone, and NuVasive; and receives royalties from SI Bone as well as royalties, stock/stock options, and research support from NuVasive. Dr. Snyder serves as a consultant for Medtronic, Globus, and NuVasive; and has research support from Biogen.Dr. Uribe serves as a consultant for Mainstay Medical, Viseon, Misonix, SI Bone, and NuVasive; and receives royalties from SI Bone as well as royalties, stock/stock options, and research support from NuVasive. Dr. Snyder serves as a consultant for Medtronic, Globus, and NuVasive; and has research support from Biogen., (© 2022, The Authors.)

The lateral access approach for L1-2 interbody placement or other levels at or near the thoracolumbar junction may be difficult without proper knowledge and visualization of anatomy. Specifically, understanding where the fibers of the diaphragm travel and avoiding injury to the diaphragm are paramount. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2221., Competing Interests: Disclosures Dr. Snyder is a consultant for Medtronic, Globus, and NuVasive and obtains research funding from Biogen. Dr. Xu is a consultant for NuVasive. Dr. Uribe receives consulting fees and royalties from NuVasive Medical, Inc., and is a consultant for Masonix, Inc., and SI Bone, Inc.Dr. Snyder is a consultant for Medtronic, Globus, and NuVasive and obtains research funding from Biogen. Dr. Xu is a consultant for NuVasive. Dr. Uribe receives consulting fees and royalties from NuVasive Medical, Inc., and is a consultant for Masonix, Inc., and SI Bone, Inc., (© 2022, The Authors.)

Robotic systems to assist with pedicle screw placement have recently emerged in the field of spine surgery. Here, the authors systematically reviewed the literature for evidence of these robotic systems and their utility. Thirty-four studies that reported the use of spinal instrumentation with robotic assistance and met inclusion criteria were identified. The outcome measures gathered included: pedicle screw accuracy, indications for surgery, rates of conversion to an alternative surgical method, radiation exposure, and learning curve. In our search there were five different robotic systems identified. All studies reported accuracy and the most commonly used accuracy grading scale was the Gertzbein Robbins scale (GRS). Accuracy of clinically acceptable pedicle screws, defined as < 2 mm cortical breech, ranged from 80% to 100%. Many studies categorized indications for robotic surgery with the most common being degenerative entities. Some studies reported rates of conversion from robotic assistance to manual instrumentation due to many reasons, with robotic failure as the most common. Radiation exposure data revealed a majority of studies reported less radiation using robotic systems. Studies looking at a learning curve effect with surgeon use of robotic assistance were not consistent across the literature. Robotic systems for assistance in spine surgery have continued to improve and the accuracy of pedicle screw placement remains superior when compared to free-hand technique, however rates of manual conversion are significant. Currently, these systems are successfully employed in various pathological entities where trained spine surgeons can be safe and accurate regardless of robotic training., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Myelopathy is a clinical diagnosis with localization of the neurological findings to the spinal cord, rather than the brain or the peripheral nervous system, and then to a particular segment of the spinal cord. Myelopathy can be the result of primary intrinsic disorders of the spinal cord or from secondary conditions, which result in extrinsic compression of the spinal cord. While the causes of myelopathy may be multiple, the acuity of presentation and symptom onset frame a practical approach to the differential diagnosis. Imaging plays a crucial role in the evaluation of myelopathy with MRI the preferred modality. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2021 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Objective: Anterior cervical discectomy and fusion (ACDF) is a common and robust procedure performed on the cervical spine. Literature on ACDF for 4 or more segments is sparse. Increasing the number of operative levels increases surgical complexity, tissue retraction, and risks of complications, particularly dysphagia. The overall risks of these complications and rates of dysphagia are not well studied for surgery on 4 or more segments. In this study, the authors evaluated their institution's perioperative experience with 4- and 5-level ACDFs., Methods: The authors retrospectively reviewed patients who underwent 4- or 5-level ACDF at their institution over a 6-year period (May 2013-May 2019). Patient demographics, perioperative complications, readmission rates, and swallowing outcomes were recorded. Outcomes were analyzed with a multivariate linear regression., Results: A total of 174 patients were included (167 had 4-level and 7 had 5-level ACDFs). The average age was 60.6 years, and 54.0% of patients (n = 94) were men. A corpectomy was performed in 12.6% of patients (n = 22). After surgery, 56.9% of patients (n = 99) experienced dysphagia. The percentage of patients with dysphagia decreased to 22.8% (37/162) at 30 days, 12.9% (17/132) at 90 days, and 6.3% (5/79) and 2.8% (1/36) at 1 and 2 years, respectively. Dysphagia was more likely at 90 days postoperatively in patients with gastroesophageal reflux (OR 4.4 [95% CI 1.5-12.8], p = 0.008), and the mean (± SD) lordosis change was greater in patients with dysphagia than those without at 90 days (19.8° ± 13.3° vs 9.1° ± 10.2°, p = 0.003). Dysphagia occurrence did not differ with operative implants, including graft and interbody type. The mean length of time to solid food intake was 2.4 ± 2.1 days. Patients treated with dexamethasone were more likely to achieve solid food intake prior to discharge (OR 4.0 [95% CI 1.5-10.6], p = 0.004). Postsurgery, 5.2% of patients (n = 9) required a feeding tube due to severe approach-related dysphagia. Other perioperative complication rates were uniformly low. Overall, 8.6% of patients (n = 15) returned to the emergency department within 30 days and 2.9% (n = 5) required readmission, whereas 1.1% (n = 2) required unplanned return to surgery within 30 days., Conclusions: This is the largest series of patients undergoing 4- and 5-level ACDFs reported to date. This procedure was performed safely with minimal intraoperative complications. More than half of the patients experienced in-hospital dysphagia, which increased their overall length of stay, but dysphagia decreased over time.

Introduction: Neurosurgical guidelines recommend maintaining mean arterial pressure (MAP) between 85 and 90 mm Hg following acute spinal cord injury (SCI). In our hospital, SCI patients receive orders for MAP targeting for 72 hours following admission, but it is unclear how often the patient's MAP meets the target and whether or not this affects outcome. We hypothesized that the proportion of MAP measurements ≥85 mm Hg would be associated with neurologic recovery., Methods: Spinal cord injury patients with blunt mechanism of injury admitted between 2014 and 2019 were identified from the registry of a level 1 trauma center. Proportion of MAP values ≥85 mm Hg was calculated for each patient. Neurologic improvement, as measured by positive change in American Spinal Injury Association (ASIA) impairment scale by ≥1 level from admission to discharge was evaluated with respect to proportion of elevated MAP values., Results: A total of 136 SCI patients were evaluated. Average proportion of elevated MAP values was 75%. Admission ASIA grades were as follows: A, 30 (22.1%); B, 20 (14.7%); C, 28 (20.6%); and D, 58 (42.6%). One hundred six patients (77.9%) required vasopressors to elevate MAP (ASIA A, 86.7%; B, 95.0%; C, 92.9%; D, 60.3%). Forty patients (29.4%) were observed to have improvement in ASIA grade by discharge (admission ASIA A, 15%; B, 33%; C, 40%; D, 13%). The proportion of elevated MAP values was higher for patients with neurologic improvement (0.81 ± 0.15 vs. 0.72 ± 0.25, p = 0.014). Multivariate modeling demonstrated a significant association between proportion of elevated MAP values and neurologic improvement (p = 0.028). An interaction revealed this association to be moderated by vasopressor dose (p = 0.032)., Conclusion: The proportion of MAP measurements ≥85 mm Hg was determined to be an independent predictor of neurologic improvement. Increased vigilance regarding MAP maintenance above 85 mm Hg is warranted to optimize neurologic recovery following SCI., Level of Evidence: Therapeutic/care management, level IV., (Copyright © 2020 American Association for the Surgery of Trauma.)

Working students face incredible demands on their time and resources, yet little research exists assessing the degree to which they are able to recover from their demands. The current study aimed to determine the extent to which different types of psychological detachment-detachment from work as well as detachment from school-contribute to the well-being of working students, and whether work can serve as an opportunity to recover from school and vice versa. An additional focus of the study was how perceived stress interacts with detachment both from school and from work to impact well-being. To investigate these questions, data were collected daily for 12 days from 268 undergraduate students who were also employed. Results revealed that neither psychological detachment from work nor from school is beneficial, with psychological detachment from work even having a negative relationship with vigor. However, perceived stress due to school did interact with psychological detachment from school, such that detachment had a stronger impact on vigor and fatigue on days when individuals experienced more stress. A key takeaway from this study is the need for future research on psychological detachment for working students to separate detachment from work and detachment from school. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB-expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB-expressing Tregs represents a strategy with potential activity across cancer types.

Background: Optimal management of patients with extracranial blunt cerebrovascular injury (BCVI) remains controversial, with both anticoagulation and antiplatelet therapy being recommended. The purpose of this study was to evaluate the efficacy and safety of using acetylsalicylic acid (ASA) in the management of BCVI., Methods: Patients with BCVI were identified from the registry of a Level 1 trauma center between 2010 and 2017. Digital imaging and electronic medical records were reviewed for patient information including demographic characteristics, injury type, therapy, outcomes, and follow-up., Results: Over the study period, 13,578 patients were admitted following blunt trauma, with 94 (0.7%) having confirmed BCVI (mean age, 42 years; 72% male). Mean Injury Severity Score and Glasgow Coma Score were 27 and 10, respectively. BCVI was identified in 130 vessels with Biffl grade I (38%) and grade II injury (29%) being most common. Twelve (13%) patients experienced an ischemic event, but only 3 events occurred after diagnosis. ASA was primary treatment for 56 (60%) patients. Thirty patients (32%) received no treatment; 21 patients died within 24 hours of primary injury. Only 4 patients had ASA contraindications. Four patients (7%) had ASA-related complications; there were 2 cases of intracranial hemorrhage progression and 2 cases of gastrointestinal bleeding. Follow-up vascular imaging at a mean of 36 days demonstrated stable or improved levels of BCVI in 94% of patients., Conclusions: An ASA-based management strategy for BCVI was efficacious and relatively safe in this study. This approach may be the preferred treatment for BCVI, but confirmation is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Digital microscopy (DM) has been employed for primary diagnosis in human medicine and for research and teaching applications in veterinary medicine, but there are few veterinary DM validation studies. Region of interest (ROI) digital cytology is a subset of DM that uses image-stitching software to create a low-magnification image of a slide, then selected ROI at higher magnification, and stitches the images into a relatively small file of the embedded magnifications. This study evaluated the concordance of ROI-DM compared to traditional light microscopy (LM) between 2 blinded clinical pathologists. Sixty canine and feline cytology samples from a variety of anatomic sites, including 31 cases of malignant neoplasia, 15 cases of hyperplastic or benign neoplastic lesions, and 14 infectious/inflammatory lesions, were evaluated. Two separate nonblinded adjudicating clinical pathologists evaluated the reports and diagnoses and scored each paired case as fully concordant, partially concordant, or discordant. The average overall concordance (full and partial concordance) for both pathologists was 92%. Full concordance was significantly higher for malignant lesions than benign. For the 40 neoplastic lesions, ROI-DM and LM agreed on general category of tumor type in 78 of 80 cases (98%). ROI-DM cytology showed robust concordance with the current gold standard of LM cytology and is potentially a viable alternative to current LM cytology techniques.

With a specific focus on the Native American population, the current study investigated the structure of ethnic identity, measured by the Multigroup Ethnic Identity Measure, using a bifactor model across Native American ( n = 307), Asian ( n = 348), and White ( n = 549) undergraduate students. We further investigated measurement invariance across ethnic groups that shared the same factor structure. The results indicated that ethnic identity can be modeled by a bifactor structure with a general factor and two group factors, affective pride and exploration, for Native American and Asian respondents but not White respondents. In addition, measurement invariance tests supported partial weak invariance between the Native American group and the Asian group. The current findings suggest that comparisons of ethnic identity scores across ethnic groups should be treated with caution.

Objective: Minimally invasive transforaminal interbody fusion techniques vary among surgeons. One decision point is whether to perform a unilateral facetectomy (UF), a unilateral facetectomy plus partial contralateral facetectomy (UF/PF), or a complete bilateral facetectomy (CBF). The authors therefore compared the biomechanical benefits of all 3 types of facetectomies to determine which approach produces improved biomechanical outcomes., Methods: Seven human cadaveric specimens (L3-S1) were potted and prepped for UF, with full facet removal, hemilaminectomy, discectomy, and pedicle screw placement. After distraction, a fixed interbody spacer was placed, and compression was performed. A final fixation configuration was performed by locking the rods across the screws posteriorly with bilateral compression. Final lordosis angle and change and foraminal height were measured, and standard nondestructive flexibility tests were performed to assess intervertebral range of motion (ROM) and compressive stiffness. The same procedure was followed for UF/PF and CBF in all 7 specimens., Results: All 3 conditions demonstrated similar ROM and compressive stiffness. No statistically significant differences occurred with distraction, but CBF demonstrated significantly greater change than UF in mean foraminal height after bilateral posterior compression (1.90 ± 0.62 vs 1.00 ± 0.45 mm, respectively, p = 0.04). With compression, the CBF demonstrated significantly greater mean ROM than the UF (2.82° ± 0.83° vs 2.170° ± 1.10°, p = 0.007). The final lordosis angle was greatest with CBF (3.74° ± 0.70°) and lowest with UF (2.68° ± 1.28°). This finding was statistically significant across all 3 conditions (p ≤ 0.04)., Conclusions: Although UF/PF and CBF may require slightly more time and effort and incur more risk than UF, the potential improvement in sagittal balance may be worthwhile for select patients.

Nontraumatic neck pain is a leading cause of disability, with nearly 50% of individuals experiencing ongoing or recurrent symptoms. Radiographs are appropriate as initial imaging for cervical or neck pain in the absence of "red flag" symptoms or if there are unchanging chronic symptoms; however, spondylotic changes are commonly identified and may result in both false-positive and false-negative findings. Noncontrast CT can be complementary to radiographs for evaluation of new or changing symptoms in the setting of prior cervical spine surgery or in the assessment of extent of ossification in the posterior longitudinal ligament. Noncontrast MRI is usually appropriate for assessment of new or increasing radiculopathy due to improved nerve root definition. MRI without and with contrast is usually appropriate in patients with new or increasing cervical or neck pain or radiculopathy in the setting of suspected infection or known malignancy. Imaging may be appropriate; however, it is not always indicated for evaluation of cervicogenic headache without neurologic deficit. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2019 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Objective: Transforaminal lumbar interbody fusion (TLIF) is commonly used for lumbar fusion, such as for foraminal decompression, stabilization, and improving segmental lordosis. Although many options exist, surgical success is contingent on matching design strengths with surgical goals. The goal in the present study was to investigate the effects of an expandable interbody spacer and 2 traditional static spacer designs in terms of stability, compressive stiffness, foraminal height, and segmental lordosis., Methods: Standard nondestructive flexibility tests (7.5 N⋅m) were performed on 8 cadaveric lumbar specimens (L3-S1) to assess intervertebral stability of 3 types of TLIF spacers at L4-5 with bilateral posterior screw-rod (PSR) fixation. Stability was determined as range of motion (ROM) in flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Compressive stiffness was determined with axial compressive loading (300 N). Foraminal height, disc height, and segmental lordosis were evaluated using radiographic analysis after controlled PSR compression (170 N). Four conditions were tested in random order: 1) intact, 2) expandable interbody cage with PSR fixation (EC+PSR), 3) static ovoid cage with PSR fixation (SOC+PSR), and 4) static rectangular cage with PSR fixation (SRC+PSR)., Results: All constructs demonstrated greater stability than the intact condition (p < 0.001). No significant differences existed among constructs in ROM (FE, AR, and LB) or compressive stiffness (p ≥ 0.66). The EC+PSR demonstrated significantly greater foraminal height at L4-5 than SRC+PSR (21.1 ± 2.6 mm vs 18.6 ± 1.7 mm, p = 0.009). EC+PSR demonstrated higher anterior disc height than SOC+PSR (14.9 ± 1.9 mm vs 13.6 ± 2.2 mm, p = 0.04) and higher posterior disc height than the intact condition (9.4 ± 1.5 mm vs 7.1 ± 1.0 mm, p = 0.002), SOC+PSR (6.5 ± 1.8 mm, p < 0.001), and SRC+PSR (7.2 ± 1.2 mm, p < 0.001). There were no significant differences in segmental lordosis among SOC+PSR (10.1° ± 2.2°), EC+PSR (8.1° ± 0.5°), and SRC+PSR (11.1° ± 3.0°) (p ≥ 0.06)., Conclusions: An expandable interbody spacer provided stability, stiffness, and segmental lordosis comparable to those of traditional nonexpandable spacers of different shapes, with increased foraminal height and greater disc height. These results may help inform decisions about which interbody implants will best achieve surgical goals.

Methoxyfenozide is an insect growth regulator (IGR) commonly used in agriculture to simultaneously control pests and preserve beneficial insect populations; however, its impact on honey bees in not fully understood. We conducted field and laboratory experiments to investigate bee health in response to field-relevant concentrations of this pesticide. Significant effects were observed in honey bee colony flight activity and thermoregulation after being exposed over 9 weeks to supplemental protein patty containing methoxyfenozide. Compared to bee colonies in the control group, colonies fed pollen patty with 200 ppb methoxyfenozide (as measured by residue analysis) had: 1) a significantly reduced rate of weight loss due to forager departure in the morning; and 2) higher temperature variability during the winter. Colonies in the 100 ppb (as measured by residue analysis) treatment group had values between the 200 ppb group and control for both response variables. The dusk break point, which is the time associated with the end of forager return, differed among all treatment groups but may have been confounded with direction the hives were facing. Bee colony metrics of adult bee mass and brood surface area, and measurements of bee head weight, newly-emerged bee weight, and hypopharyngeal gland size were not significantly affected by methoxyfenozide exposure, suggesting that there may be significant effects on honey bee colony behavior and health in the field that are difficult to detect using standard methods for assessing bee colonies and individuals. The second experiment was continued into the following spring, using the same treatment groups as in the fall. Fewer differences were observed among groups in the spring than the fall, possibly because of abundant spring forage and consequent reduced treatment patty consumption. Residue analyses showed that: 1) observed methoxyfenozide concentrations in treatment patty were about 18-60% lower than the calculated concentrations; 2) no residues were observed in wax in any treatment; and 3) methoxyfenozide was detected in bee bread only in the 200 ppb treatment group, at about 1-2.5% of the observed patty concentration., Competing Interests: The authors have declared that no competing interests exist.

Minimally invasive surgery (MIS) techniques may enable faster patient recovery and reduce the incidence of postoperative infections. Image-guided approaches to spinal instrumentation and interbody fusion have gained popularity in MIS, reducing radiation exposure and improving screw placement accuracy. Use of a novel computed tomography (CT) navigation-based robotic arm provides for live image-guided surgery, with the potential for augmenting existing MIS approaches and improving the accuracy of instrumentation placement. We report on the surgical technique of MIS transforaminal lumbar interbody fusion (TLIF) performed with the assistance of a new robotic device (ExcelsiusGPS, Globus Medical Inc, Audubon, Pennsylvania) and intraoperative CT guidance in a patient with single-level lumbar spondylolisthesis. The patient gave written informed consent before treatment. Institutional review board approval was deemed unnecessary. The patient was positioned prone on the operating room table, and an intraoperative CT was obtained with stereotactic arrays placed bilaterally in the posterior superior iliac spine. Screw trajectories were planned using the ExcelsiusGPS software and placed percutaneously with the robotic arm without using a Kirschner wire. Interbody placement was performed via an expandable retractor after muscle dilation. Screw placement accuracy was determined with postoperative CT, which demonstrated good screw positioning without breach. The patient recovered well and was discharged home without complications. The combined use of the new robotic device and intraoperative CT enables accurate and safe fixation for the treatment of symptomatic lumbar spondylolisthesis. The operative video demonstrates the technical nuances of positioning, stereotactic marker placement, work flow, and screw placement. Used with permission from Barrow Neurological Institute, Phoenix, Arizona., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Objective: The Barrow Innovation Center comprises an educational program in medical innovation that enables residents to identify problems in patient care and rapidly develop and implement solutions to these problems. Residents involved in this program noted an elevated risk of iatrogenic spinal cord injury during posterior cervical and thoracic procedures. The objective of this study was to describe this complication, and a novel solution was developed through a new innovation training program., Methods: A case report demonstrates the risk of iatrogenic spinal cord injury during posterior cervical decompression and fusion. Solutions to this problem were developed at the innovation center via an iterative process of prototype creation, cadaveric testing, and redesign. Patent law students who partnered with the center wrote and filed a provisional patent protecting the novel prototype designs., Results: The concept of a protective shield for the spinal cord was developed, and within only 6 weeks the devices were provisionally patented and used in the operating room. This device was named the Myeloshield. Initial clinical experience indicates that the Myeloshield can be used without impeding the flow of surgery and has the potential to prevent iatrogenic spinal cord injury; this experience is presented through 2 case reports demonstrating the use of Myeloshields in the operating room., Conclusions: This report demonstrates how programs like the Barrow Innovation Center can provide neurosurgery residents with a unique educational experience in medical device innovation and intellectual property development and can serve as an avenue of surgical quality improvement and problem solving., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Research pertaining to STEM interest and persistence continues to be a top priority in the educational research arena. The current study employed a person-centered approach to examine the impact of math self-efficacy and various distal predictors, such as individuals' demographic information, beliefs about math, and social group identification, on STEM interest and intentions. Specifically, we conducted a latent profile analysis (LPA), thereby inferring three homogeneous subgroups of individuals or latent classes from their response patterns on the 18-item sources of math self-efficacy measure. Our analyses showed that individuals' ethnicity, implicit theories of math ability, and other group orientation were predictive of class membership (Mastery, Moderate, and Unconfident). We also found that there were significant differences in interest in STEM subjects, interest in STEM activities, individuals' majors, and retention grade point average across the three latent classes. Our findings support the importance of math self-efficacy in choice of major as well as overall academic performance regardless of whether a student is in a STEM field or a non-STEM field.

The nurse hypopharyngeal glands produce the protein fraction of the worker and royal jelly that is fed to developing larvae and queens. These paired glands that are located in the head of the bee are highly sensitive to the quantity and quality of pollen and pollen substitutes that the nurse bee consumes. The glands get smaller when nurses are fed deficient diets and are large when they are fed complete diets. Because nurse hypopharyngeal gland size is a robust indicator of nurse nutrition, it is essential that those studying honey bee nutrition know how to measure these glands. Here, we provide detailed methods for dissecting, staining, imaging, and measuring nurse bee hypopharyngeal glands. We present comparisons of unstained and stained tissue and data that were used to study the impact of pollen on gland size. This method has been used to test how diet impacts hypopharyngeal gland size but has further use for understanding the role of these glands in hive health.

Background and Importance: Endovascular therapy has proven to be a safe, minimally invasive treatment for multiple etiologies, but proper precautions must be taken to avoid complications. When complications occur, they should be promptly identified and corrected when possible. This case report describes endovascular stents misplaced into the epidural spinous venous plexus rather than the iliofemoral arteries, causing cauda equina syndrome, as well as the spinal procedure performed to treat the resulting spinal canal compression., Clinical Presentation: A 67-yr-old man had undergone what he thought was iliofemoral arterial stenting at an outside hospital for peripheral vascular disease. He presented 8 d later to our hospital with cauda equina syndrome comprising back pain, right L5 radiculopathy, perianal numbness, urinary retention, and constipation. Scans demonstrated stents deployed into the venous system, traversing the spinal canal and the right L5-S1 neural foramen, resulting in severe spinal canal stenosis, right L5-S1 foraminal stenosis, and moderate left S1-S2 foraminal stenosis. The patient underwent an L5-S1 laminectomy with full right L5-S1 facetectomy and left S1-S2 medial facetectomy, with associated L5-S1 posterolateral fusion with fixation to remove the stent and decompress the neural elements., Conclusion: Although stent misplacement is an uncommon complication of endovascular therapy, this case demonstrates the importance of ensuring access to the proper vessel before stent placement. Once this complication was recognized, safe removal of the stents was possible and the patient demonstrated meaningful postoperative improvement in symptoms and strength.

Minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) is a well-accepted procedure with good outcomes. Robotics has the potential to augment these outcomes. This video demonstrates and discusses how surgeons can implement the use of a robotic device in an MIS TLIF workflow. The planning software and robotic arm guidance allow the surgeon to use intraoperative CT to guide the placement of pedicle screws in an MIS TLIF with optimal trajectory and decreased radiation. As robotic technology continues to improve, developing safe workflows that integrate robotics with currently well-established techniques should improve patient outcomes. The video can be found here: https://youtu.be/rJWOa6XVLW0 .

OBJECTIVE Fusiform cerebral aneurysms represent a small portion of intracranial aneurysms; differ in natural history, anatomy, and pathology; and can be difficult to treat compared with saccular aneurysms. The purpose of this study was to examine the techniques of treatment of ruptured and unruptured fusiform intracranial aneurysms and patient outcomes. METHODS In 45 patients with fusiform aneurysms, the authors retrospectively reviewed the presentation, location, and shape of the aneurysm; the microsurgical technique; the outcome at discharge and last follow-up; and the change in the aneurysm at last angiographic follow-up. RESULTS Overall, 48 fusiform aneurysms were treated in 45 patients (18 male, 27 female) with a mean age of 49 years (median 51 years; range 6 months-76 years). Twelve patients (27%) had ruptured aneurysms and 33 (73%) had unruptured aneurysms. The mean aneurysm size was 8.9 mm (range 6-28 mm). The aneurysms were treated by clip reconstruction (n = 22 [46%]), clip-wrapping (n = 18 [38%]), and vascular bypass (n = 8 [17%]). The mean (SD) hospital stay was 19.0 ± 7.4 days for the 12 patients with subarachnoid hemorrhage and 7.0 ± 5.6 days for the 33 patients with unruptured aneurysms. The mean follow-up was 38.7 ± 29.5 months (median 36 months; range 6-96 months). The mean Glasgow Outcome Scale score for the 12 patients with subarachnoid hemorrhage was 3.9; for the 33 patients with unruptured aneurysms, it was 4.8. No rehemorrhages occurred during follow-up. The overall annual risk of recurrence was 2% and that of rehemorrhage was 0%. CONCLUSIONS Fusiform and dolichoectatic aneurysms involving the entire vessel wall must be investigated individually. Although some of these aneurysms may be amenable to primary clipping and clip reconstruction, these complex lesions often require alternative microsurgical and endovascular treatment. These techniques can be performed with acceptable morbidity and mortality rates and with low rates of early rebleeding and recurrence.

Mounting evidence demonstrates that CD8 + CD122 + T cells have suppressive properties with the capacity to inhibit T cell responses. Therefore, these cells are rational targets for cancer immunotherapy. Here, we demonstrate that CD122 monoclonal antibody (mAb; aCD122) therapy significantly suppressed tumor growth and improved long-term survival in tumor-bearing mice. This therapeutic effect correlated with enhanced polyfunctional, cytolytic intratumoral CD8 + T cells and a decrease in granulocytic myeloid-derived suppressor cells (G-MDSCs). In addition, aCD122 treatment synergized with a vaccine to augment vaccine-induced antigen (Ag)-specific CD8 + T cell responses, reject established tumors and generate memory T cells. Furthermore, aCD122 mAb synergized with an anti-GITR (aGITR) mAb to confer significant control of tumor growth. These results suggest CD122 might be a promising target for cancer immunotherapy, either as a single agent or in combination with other forms of immunotherapy., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed by the authors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

One of the primary objectives of the Oncology Pathology Working Group (OPWG), a joint initiative of the Veterinary Cancer Society and the American College of Veterinary Pathologists, is for oncologists and pathologists to collaboratively generate consensus documents to standardize aspects of and provide guidelines for oncologic pathology. Consensus is established through review of relevant peer-reviewed literature relative to a subgroup's particular focus. In this document, the authors provide descriptions of the literature reviewed, the review process, and a summary of the information gathered on immunocytochemistry. The intent of this publication is to help educate practitioners and pathologists on the process of immunocytochemistry and to provide a guide for the use of this technique in veterinary medicine. This document represents the opinions of the working group and the authors and does not constitute a formal endorsement by the American College of Veterinary Pathologists or the Veterinary Cancer Society., (© 2016 John Wiley & Sons Ltd.)

Specification search problems refer to two important but under-addressed issues in testing for factorial invariance: how to select proper reference indicators and how to locate specific non-invariant parameters. In this study, we propose a two-step procedure to solve these issues. Step 1 is to identify a proper reference indicator using the Bayesian structural equation modeling approach. An item is selected if it is associated with the highest likelihood to be invariant across groups. Step 2 is to locate specific non-invariant parameters, given that a proper reference indicator has already been selected in Step 1. A series of simulation analyses show that the proposed method performs well under a variety of data conditions, and optimal performance is observed under conditions of large magnitude of non-invariance, low proportion of non-invariance, and large sample sizes. We also provide an empirical example to demonstrate the specific procedures to implement the proposed method in applied research. The importance and influences are discussed regarding the choices of informative priors with zero mean and small variances. Extensions and limitations are also pointed out.

Tumor progression is facilitated immunologically by mechanisms that include low antigen expression, an absence of coimmunostimulatory signals, and the presence of regulatory T cells (Tregs), all of which act to suppress and restrict effector T cells in the tumor. It may be possible to overcome these conditions by a combination of modulatory immunotherapy agents and tumor-antigen targeting to activate and drive effective antitumor T cell responses. Here, we demonstrated that co-administration of aGITR and aPD-1 monoclonal antibodies (mAb) in combination with a peptide vaccine (Vax) in mice bearing established tumors significantly delayed tumor growth and induced complete regression in 50% of the mice. This response was associated with increased expansion and functionality of potent Ag-specific polyfunctional CD8+ T cells, reduced Tregs, and the generation of memory T cells. Tumor regression correlated with the expansion of tumor-infiltrating antigen-specific CD8+ effector memory T cells, as depletion of this cell population significantly reduced the effectiveness of the triple combination Vax/aGITR/aPD-1 therapy. These findings support the concept that dual aGITR/aPD-1 combination with cancer vaccines may be a novel strategy against poorly immunogenic tumors.

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.