Supporting generalization in non-human primate behavior by tapping into structural knowledge: Examples from sensorimotor mappings, inference, and decision-making.

The complex behaviors we ultimately wish to understand are far from those currently used in systems neuroscience laboratories. A salient difference are the closed loops between action and perception prominently present in natural but not laboratory behaviors. The framework of reinforcement learning and control naturally wades across action and perception, and thus is poised to inform the neurosciences of tomorrow, not only from a data analyses and modeling framework, but also in guiding experimental design. We argue that this theoretical framework emphasizes active sensing, dynamical planning, and the leveraging of structural regularities as key operations for intelligent behavior within uncertain, time-varying environments. Similarly, we argue that we may study natural task strategies and their neural circuits without over-training animals when the tasks we use tap into our animal's structural knowledge. As proof-of-principle, we teach animals to navigate through a virtual environment - i.e., explore a well-defined and repetitive structure governed by the laws of physics - using a joystick. Once these animals have learned to 'drive', without further training they naturally (i) show zero- or one-shot learning of novel sensorimotor contingencies, (ii) infer the evolving path of dynamically changing latent variables, and (iii) make decisions consistent with maximizing reward rate. Such task designs allow for the study of flexible and generalizable, yet controlled, behaviors. In turn, they allow for the exploitation of pillars of intelligence - flexibility, prediction, and generalization -, properties whose neural underpinning have remained elusive.

Tobacco use and surgical outcomes in patients with head and neck cancer.

BACKGROUND: Tobacco use is a risk factor for head and neck cancer, but effects on postoperative outcomes are unclear. METHODS: Patients with head and neck cancer (n = 89) were recruited before surgery. We assessed self-reported tobacco use status (never, former, or current) at study entry and recent tobacco exposure via urinary cotinine on surgery day. Outcomes included hospital length of stay (LOS) and complications. RESULTS: Most participants reported current (32.6%) or former (52.8%) tobacco use; 43.2% were cotinine-positive on surgery day. Complications occurred in 41.6% and mean LOS was 4.0 and 8.8 days in patients who received low and high acuity procedures, respectively. Current and former smokers were over 6 times more likely to have complications than never smokers (p = .03). For high acuity procedures, LOS was increased in current (by 4.4 days) and former smokers (by 2.3 days; p = .02). CONCLUSION: Tobacco use status is associated with postoperative complications and may distinguish at-risk patients.

Competing Risk Analysis of Neurologic versus Nonneurologic Death in Patients Undergoing Radiosurgical Salvage After Whole-Brain Radiation Therapy Failure: Who Actually Dies of Their Brain Metastases?

PURPOSE: To estimate the hazard for neurologic (central nervous system, CNS) and nonneurologic (non-CNS) death associated with patient, treatment, and systemic disease status in patients receiving stereotactic radiosurgery after whole-brain radiation therapy (WBRT) failure, using a competing risk model. PATIENTS AND METHODS: Of 757 patients, 293 experienced recurrence or new metastasis following WBRT. Univariate Cox proportional hazards regression identified covariates for consideration in the multivariate model. Competing risks multivariable regression was performed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for both CNS and non-CNS death after adjusting for patient, disease, and treatment factors. The resultant model was converted into an online calculator for ease of clinical use. RESULTS: The cumulative incidence of CNS and non-CNS death at 6 and 12 months was 20.6% and 21.6%, and 34.4% and 35%, respectively. Patients with melanoma histology (relative to breast) (aHR 2.7, 95% CI 1.5-5.0), brainstem location (aHR 2.1, 95% CI 1.3-3.5), and number of metastases (aHR 1.09, 95% CI 1.04-1.2) had increased aHR for CNS death. Progressive systemic disease (aHR 0.55, 95% CI 0.4-0.8) and increasing lowest margin dose (aHR 0.97, 95% CI 0.9-0.99) were protective against CNS death. Patients with lung histology (aHR 1.3, 95% CI 1.1-1.9) and progressive systemic disease (aHR 2.14, 95% CI 1.5-3.0) had increased aHR for non-CNS death. CONCLUSION: Our nomogram provides individual estimates of neurologic death after salvage stereotactic radiosurgery for patients who have failed prior WBRT, based on histology, neuroanatomical location, age, lowest margin dose, and number of metastases after adjusting for their competing risk of death from other causes.

Type 2 Endometrial Cancer is Associated With a High Density of Tumor-Associated Macrophages in the Stromal Compartment.

INTRODUCTION: Tumor-associated macrophages (TAMs) play a pivotal role in orchestrating the microenvironment. The TAMs differentially polarize into M1 or M2 macrophages with distinct actions. The aim of our work is to characterize density, subtype, and location of TAMs in endometrial hyperplasia and cancer. METHODS: Formalin-fixed, paraffin-embedded sections of hyperplasia (n = 5), type 1 (n = 5), and type 2 (n = 5) endometrial cancer were stained with anti-CD68 and anti-CD163 monoclonal antibodies as markers for total TAMs and M2 TAMs, respectively. Macrophages were counted at 40× magnification in 10 high-power fields (HPFs) per slide by 4 observers. Repeated measures models were constructed to determine the relationships between macrophages and lesion categories. RESULTS: Most CD68+ TAMs were located in the stromal (mean = 41.0/HPF) compared to epithelial (mean = 11.0/HPF) or luminal (mean = 11.6/HPF) compartments. Similar but reduced findings were observed for CD163+ (M2 subtype) TAMs. The CD68+ stromal TAM density was highest in patients with type 2 cancers (mean = 54.0/HPF) compared to those with type 1 cancers (mean = 35.5/HPF) and hyperplasia (mean = 29.0/HPF). Women with hyperplasia had more CD163+ (M2 subtype) TAMs (26.7/HPF) than patients with either type of cancer (type 1 = 12.5/HPF and type 2 = 11.5/HPF). Based on the repeated measures models, type 2 cancers had 38.6/HPF more CD68+ TAMs than type 1 cancers (P < .0001) and type 1 and type 2 cancers had similar numbers of CD163+ TAMs (P = .27). CONCLUSIONS: Type 2 cancers have nearly twice the TAM density of type 1 cancers. This difference may be due to M1 macrophage predominance in the stroma of type 2 cancers.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in sarcomatosis from gastrointestinal stromal tumor.

The role of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) procedures in the management of patients with gastrointestinal stromal tumor (GIST)-induced sarcomatosis that is refractory to tyrosine kinase inhibitors (TKI) is not well defined. A retrospective analysis of a prospective database of 1070 CRS/HIPEC procedures was performed. Demographics, Eastern Cooperative Oncology Group performance status, resection status, morbidity, mortality, perioperative use of targeted therapies, and overall survival were analyzed. Since 1992, 18 CRS/HIPEC procedures were performed for peritoneal dissemination of GIST. Fifty per cent of these cases were performed before the introduction of TKIs. R0/1 resection was achieved in 72 per cent, whereas 63 per cent of patients were treated with neoadjuvant and/or adjuvant targeted therapy. Thirty-day morbidity and mortality were 33.3 and 5.6 per cent, respectively. Median overall survival after CRS/HIPEC was 3.33 years with 3-year survival of 56 per cent. Median survival in those who did not receive targeted therapy was 1.04 versus 7.9 years for those treated with TKI and cytoreduction. Median postsurgical survival for those treated preoperatively with progression on TKI treatment was 1.35 years versus not reached in those on TKI therapy without progression. Primary therapy for patients with disseminated GIST should be TKI therapy. However, in patients with sarcomatosis from GIST, cytoreduction should be considered before developing TKI resistance. Progression on TKI is associated with poor outcomes even after complete cytoreduction.

Anatomic study of the distance between the articular eminence and foramen spinosum and foramen spinosum and petrotympanic fissure.

PURPOSE: The middle meningeal artery is in close proximity to the medial aspect of the temporomandibular joint (TMJ). A major potential complication of surgery in the area of the TMJ is possible severance of the middle meningeal artery. An understanding of the relationship of the middle meningeal artery to easily identifiable landmarks lateral to the TMJ can help prevent the complications associated with TMJ surgery. The aim of the present study was to define the location of the middle meningeal artery by relating the distance between the easily identifiable bony landmarks of the articular eminence, petrotympanic fissure, and foramen spinosum. MATERIALS AND METHODS: Using a cross-sectional study design, we selected dried skulls from the Hamman-Todd skeleton collection at the Cleveland Museum of Natural History that were older than 20 years of age at death. The primary study variables were the distances between the articular eminence and foramen spinosum and the foramen spinosum and petrotympanic fissure. To appropriately analyze the variables, stratifications of age, gender, race, and anatomic location were applied. To measure the relationship between the stratifications and distances, a multivariate analysis of variance test was performed. The statistical results were deemed significant at P < .05. RESULTS: The sample consisted of 354 skulls or a total of 708 complexes. In analyzing the data, we noted that the only stratifications that bore any statistical significance were gender, with P < .0001, and the race-distance correlation, with a P value of .0007. CONCLUSIONS: The results of the present study suggest a definite difference in regard to gender on the distance between both sets of anatomic landmarks. Future studies could be tailored to further explore the effect of age on the distance, as a slight correlation was noted in our study.

Relationship of race-ethnicity, body mass index, and economic strain with longitudinal self-report of physical functioning: the Study of Women's Health Across the Nation.

PURPOSE: This study examined progression and improvement of physical functioning limitations during the mid-life and whether race-ethnicity, economic strain, or body mass index were associated with these changes. METHODS: Women from the Study of Women's Health Across the Nation with one or more measure of self-reported physical functioning, categorized as no, some, or substantial limitations, between study visits 4 and 12 were included (n = 2497). RESULTS: When women were aged 56-66 years, almost 50% reported limitations in functioning. African American women were more likely to report substantial (odds ratio, 1.63; 95% confidence interval, 1.06-2.52) and Chinese women were more likely to report some limitations (odds ratio, 2.03; 95% CI, 1.22-3.36) compared with Caucasian women. Economic strain and obesity predicted limitations. The probability of worsening ranged from 6% to 22% and of improving ranged from 11% to 30%. Caucasian and Japanese women had the highest probability of remaining fully functional (80% and 84%, respectively) compared with 71% of African American women. CONCLUSIONS: Race-ethnicity, obesity, and economic strain were associated with prevalence and onset of physical functioning limitations. Functional improvement is common, even among vulnerable subgroups of women. Future studies should characterize predictors of decline and improvement so that interventions can sustain functioning even in the context of many known immutable risk factors.