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

The value of using a brain laser interstitial thermal therapy (LITT) system in patients presenting with high grade gliomas where maximal safe resection may not be feasible

BACKGROUND: The objective of this analysis was to determine the value (incremental cost/increment benefit) of a brain LITT system versus employing current surgical options recommended by NCCN guidelines, specifically open resection (i.e. craniotomy) methods or biopsy (collectively termed CURRENT TREATMENTS) in patients where maximal safe resection may not be feasible. As has been demonstrated in the literature, extent of resection/ablation with minimal complications are independently related to overall survival. METHODS: A cost effectiveness analysis from a societal perspective was employed using TreeAge Pro 2014 software. Direct costs (using national average Medicare reimbursement amounts), outcomes (overall survival), and value [defined as increment cost/incremental survival—evaluated as cost/life year gained (LYG)] were evaluated. Sensitivity analysis was also performed to determine which variables had the largest effect on incremental costs and outcomes. RESULTS: In the base case, the overall survival was improved with brain LITT versus CURRENT TREATMENTS by 3.07 months at an additional cost of $7508 (or$29,340/LYG). This amount was significantly less than the current international threshold value for $32,575/LYG and considerably less than the US threshold value of$50,000/LYG. This incremental cost may also qualify under NICE criteria for end of life therapies. In sensitivity analysis: As percent local recurrence GBM increased; cost of DRG25/26 increased; percent GTR increased; and gliadel use increased—the value of brain LITT improved. Additionally, in those patients where a biopsy is the only option, brain LITT extended life by 7 months. CONCLUSIONS: Brain LITT should be considered a viable option for treatment of high grade gliomas as it improves survival at a cost which appears to be of good value to society. This incremental cost is less than the international and US thresholds for good value

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

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

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

Integrated molecular analysis suggests a three-class model for low-grade gliomas: A proof-of-concept study

AbstractIntroduction: We used an integrated molecular analysis strategy to perform class discovery on a population of low-grade gliomas (astrocytomas, oligodendrogliomas, and mixed gliomas) to improve our understanding of the molecular relationships among these tumors and to reconcile genotypic relationships with current histologic and molecular strategies for tumor classification.Methods: Gene expression profiling was performed on a cross-section of World Health Organization (WHO) grades I–II gliomas. Unsupervised class discovery algorithms identified and validated tumor clusters with genotypic similarity, and these data were integrated with chromosomal copy number assays and RT-PCR data to define molecular tumor subclasses. Machine learning models allowed accurate, prospective classification of unknown tumors into these molecular subgroups. This molecular classification model was compared to current histologic (WHO) and molecular pathologic (chromosome 1p and 19q deletions, p53 alterations, and Ki-67 expression) methods for glioma classification.Results: Molecular class discovery suggested a three-class model for low-grade gliomas. One discrete cluster of gliomas identified the pilocytic astrocytomas, a second grouped the 1p/19q codeleted oligodendrogliomas, and the mixture of remaining 1p/19q intact gliomas, including astrocytomas, oligodendrogliomas, and oligoastrocytomas, formed a third cluster with a discrete pattern of expression.Conclusions: Integration of genomic, transcriptomic, and morphologic data for class discovery suggests a three-class model for low-grade gliomas. Class I represents tumors with molecular similarity to pilocytic astrocytomas, class II tumors are similar to 1p/19q codeleted oligodendrogliomas, and class III represents infiltrative low-grade gliomas. This classification is similar to current clinical paradigms for low-grade gliomas; our work suggests a molecular basis for such models. This classification may supplement or may serve as the basis for a molecular pathologic alternative to current grading schemes for low-grade gliomas and may highlight potential targets for future biologically based treatments or strategies for future clinical trials

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