Content Externalism and Self-Knowledge

There appears to be a tension between two widely held philosophical theses: content externalism and what is often called “privileged access”. The first is the metaphysical thesis that the contents of many propositional attitude-types are at least partially determined by properties external to the thinking subject. The second is the epistemological thesis that we have a priori access to the contents of our own propositional attitudes. Those who hold that at least one of these theses must be false are called incompatibilists. My goal is to show that the incompatibilists are wrong, that content externalism and privileged access can both be true. In Chapter 1, I briefly introduce content externalism and review the source of the alleged tension between the latter and privileged access. In Chapter 2, I address the so-called “discrimination argument” for incompatibilism. This argument appeals to the fact that, if content externalism is true, then we will not always be able to discriminate one thought-type from another. This generates problems for privileged access if we think that knowledge requires the ability to discriminate between relevant alternatives. I argue, however, that knowledge does not require such an ability. In Chapter 3, I address Jessica Brown’s illusion argument” for incompatibilism. While this argument might show that singular externalism is incompatible with privileged access, I argue that it does not generalize to other forms of content externalism. In Chapter 4 I evaluate Boghossian’s “memory argument”. First, I draw on existing criticism to show that the original 1989 version of the argument fails because it relies on false premises about memory. I then consider and reject the possibility, originally proposed by Sanford Goldberg, that the argument can be reconstructed without these false premises. Finally, in Chapter 5, I discuss and evaluate McKinsey’s reductio. First, I argue that the externalist cannot be expected to accept the closure principle on which McKinsey relies. Second, I argue that though the compatibilist may be committed to the apriority of certain environmental propositions, these propositions are modest enough that it is not obviously absurd to suppose that they might be a priori

Laser Interstitial Thermal Therapy in Glioblastoma

Laser interstitial thermal therapy is a minimally invasive ablative technique that continues to gain popularity in treatment of a variety of intracranial and spinal disorders. In the field of neuro-oncology it continues to be used for treatment of a variety of intracranial neoplasms, including glioblastoma—the most common malignant primary brain tumor. Maximizing the extent of resection in patients with glioblastoma was shown to prolong patient survival. Many patients present, however, with tumors that are nonresectable due to proximity to eloquent cortical or subcortical areas, or involvement of deep brain structures. LITT procedure, on the other hand, is minimally invasive and involves placing a laser catheter under stereotactic guidance and monitoring the size of the lesion produced as a result of laser ablation using MR thermography in real time. Therefore, a number of studies explored the potential of laser ablation to accomplish significant cytoreduction and thus potentially improve patient’s outcomes and prolong survival. The following chapter will review the principles of laser ablation and its current role in treatment of glioblastoma

Laser Ablation in Neuro-oncology

Laser interstitial thermal therapy (LITT) has emerged as a potential tool in the armamentarium of neurosurgeons managing patients with deep-seated and difficult-to-access brain tumors. Advances in stereotactic neurosurgery coupled with neuroimaging tools have led to the resurgence of interest in laser therapy for a variety of neurosurgical indications. Stereotactic placement of laser probe using minimally invasive techniques and the ability to monitor the tissue ablation in real time using MR thermometry are two distinct advantages of LITT. Patients with recurrent gliobastoma multiforme (GBM) or newly diagnosed gliomas with significant medical comorbidities, radiation necrosis, radiosurgery-resistant brain metastasis and cancer-related pain pose significant challenges in the field of neuro-oncology. LITT offers an opportunity to obtain stereotactic biopsy and cytoreduction in a minimally invasive nature. In this chapter, we have described the current applications of LITT in neuro-oncology, including malignant gliomas, brain metastatic disease, radiation necrosis and other indications such as cancer-related pain and epilepsy. We have also described the principles, technical nuances and LITT systems currently available in the clinical practice. With growing interest and acceptance of LITT in neuro-oncology, we are likely to obtain high-quality evidence supporting the utility of this modality in patients with a variety of neuro-oncological conditions in the near future

NEPC Review: Successful, Safe, and Healthy Students

The research summary Successful, Safe, and Healthy Students presents the research background for the Obama administration&rsquo;s proposals for comprehensive, community-wide services in high-poverty neighborhoods, extended learning time, family engagement and safe schools. While these policies have broad and common-sense appeal, the research supporting the particular policies proposed by the administration is weak and poorly presented in the research summary. As promising as community-wide services may be, a broad research base does not yet exist concerning how to make them successful. The research on extended learning time is also inconclusive. Family involvement is crucial to education, but the evidence for a causal link between student achievement and the type of parent involvement discussed is ambiguous and suspect. The proposals for safe schools boil down to increased local flexibility and increased gathering of survey data, neither of which can be expected to improve outcomes. Together, the administration&rsquo;s proposals would require an extensive financial commitment in order to be fully implemented, but the scope and source of these funds is not explained. Overall, the evidence provided is not sufficiently strong to justify the programs they champion. While the research summary adequately documents problems, a wiser course for public policy would be a carefully structured set of pilot studies to sharply and accurately identify solutions.</p

The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: A multicenter study

Surgical extent-of-resection has been shown to have an impact on high-grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult-to-access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA-HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA-HGGs. We retrospectively reviewed 34 consecutive DTA-HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011–December 2012) using the NeuroBlate® System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43°C for 2 min) and blue TDT line (43°C for 10 min). Volumetric analysis was performed to determine the extent-of-coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow-up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1-year estimate of OS was 68 ± 9%. Median progression-free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria—(1) <0.05 cm(3) tumor volume not covered by the yellow TDT line and (2) <1.5 cm(3) additional tumor volume not covered by the blue TDT line—had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA-HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases

Immune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p \u3c 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials

DRD4 genotype predicts longevity in mouse and human

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.Fil: Grady, Deborah L.. University of California. College of Medicine. Department of Biological Chemistry; Estados UnidosFil: Thanos, Panayotis K.. National Institute on Alcohol Abuse and Alcoholism. Laboratory of Neuroimaging; Estados Unidos. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados Unidos. Stony Brook University. Department of Psychology; Estados UnidosFil: Corrada, Maria M.. University of California. Department of Neurology; Estados UnidosFil: Barnett Jr., Jeffrey C.. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Ciobanu, Valentina. University of California. College of Medicine. Department of Biological Chemistry; Estados UnidosFil: Shustarovich, Diana. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Napoli, Anthony. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Moyzis, Alexandra G.. University of California. College of Medicine. Department of Biological Chemistry; Estados UnidosFil: Grandy, David. Oregon Health Sciences University. Physiology and Pharmacology; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Wang, Gene-Jack. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Kawas, Claudia H.. University of California. Department of Neurology; Estados UnidosFil: Chen, Chuansheng. University of California. Department of Psychology and Social Behavior; Estados UnidosFil: Dong, Qi. Beijing Normal University. National Key Laboratory of Cognitive Neuroscience and Learning; ChinaFil: Wang, Eric. University of California. College of Medicine. Department of Biological Chemistry; Estados Unidos. Aria Diagnostics Inc.; Estados Unidos. University of California. Institute of Genomics and Bioinformatics; Estados UnidosFil: Volkow, Nora D.. National Institute on Alcohol Abuse and Alcoholism. Laboratory of Neuroimaging; Estados Unidos. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados Unidos. National Institute on Drug Abuse; Estados UnidosFil: Moyzis, Robert K.. University of California. College of Medicine. Department of Biological Chemistry; Estados Unidos. Beijing Normal University. National Key Laboratory of Cognitive Neuroscience and Learning; China. University of California. Institute of Genomics and Bioinformatics; Estados Unido

Science and Ideology in Economic, Political, and Social Thought

This paper has two sources: One is my own research in three broad areas: business cycles, economic measurement and social choice. In all of these fields I attempted to apply the basic precepts of the scientific method as it is understood in the natural sciences. I found that my effort at using natural science methods in economics was met with little understanding and often considerable hostility. I found economics to be driven less by common sense and empirical evidence, then by various ideologies that exhibited either a political or a methodological bias, or both. This brings me to the second source: Several books have appeared recently that describe in historical terms the ideological forces that have shaped either the direct areas in which I worked, or a broader background. These books taught me that the ideological forces in the social sciences are even stronger than I imagined on the basis of my own experiences. The scientific method is the antipode to ideology. I feel that the scientific work that I have done on specific, long standing and fundamental problems in economics and political science have given me additional insights into the destructive role of ideology beyond the history of thought orientation of the works I will be discussing

Family History of Cancer in Benign Brain Tumor Subtypes Versus Gliomas

Purpose: Family history is associated with gliomas, but this association has not been established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%), 78 meningioma (65%), 49 pituitary adenoma (73.1%), and 152 glioma patients (58.2%). The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs) and 95% confidence intervals. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusion: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts