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Prostate cancer continues to represent a burgeoning medical problem in the United States. Recent studies suggest that gossypol, a bioactive phytochemical produced by cotton plants, is a promising agent against prostate cancer. The current studies were undertaken to examine the chemotherapeutic efficacy of gossypol on human prostate cancer cell lines and prostate tumor–initiating cells. Gossypol reduced the viability of three prostate cancer cell lines (LAPC4, PC3, and DU145) with an IC50 between 3 and 5 μmol/L. Additionally, gossypol was effective at inhibiting prostate tumor–initiating cell-driven tumor growth in a nonobese diabetic/severe combined immunodeficient xenograft model. Our integrated molecular profiling approach encompassing proteomics, activated transcription factors, and genomics suggests that the decrease in viability was associated with increased DNA damage and the induction of apoptosis. Exposure of DU145 cells to gossypol (1–10 μmol/L) resulted in the activation of 13 proteins and 7 transcription factors, and the expression of 17 genes involved in the mitochondrial pathway of apoptosis. These studies show for the first time that gossypol treatment induces DNA damage and activates p53. Collectively, these data support the use of gossypol as a novel agent for prostate cancer. Mol Cancer Ther; 9(2); 461–70

Ryan Tonkens (2009) has issued a seemingly impossible challenge, to articulate a comprehensive ethical framework within which artificial moral agents (AMAs) satisfy a Kantian inspired recipe—"rational" and "free"—while also satisfying perceived prerogatives of machine ethicists to facilitate the creation of AMAs that are perfectly and not merely reliably ethical. This series of papers meets this challenge by landscaping traditional moral theory in resolution of a comprehensive account of moral agency. The first paper established the challenge and set out autonomy in Aristotelian terms. The present paper interprets Kantian moral theory on the basis of the preceding introduction, argues contra Tonkens that an engineer does not violate the categorical imperative in creating Kantian AMAs, and proposes that a Kantian AMA is not only a possible goal for Machine ethics research, but a necessary one.

Through brain-inspired modeling studies, cognitive neurorobotics aims to resolve dynamics essential to different emergent phenomena at the level of embodied agency in an object environment shared with human beings. This article is a review of ongoing research focusing on model dynamics associated with human self-consciousness. It introduces the free energy principle and active inference in terms of Bayesian theory and predictive coding, and then discusses how directed inquiry employing analogous models may bring us closer to representing the sense of self in cognitive neurorobots. The first section quickly locates cognitive neurorobotics in the broad field of computational cognitive modeling. The second section introduces principles according to which cognition may be formalized, and reviews cognitive neurorobotics experiments employing such formalizations. The third section interprets the results of these and other experiments in the context of different senses of self, both “minimal” and “narrative” self. The fourth section considers model validity and discusses what we may expect ongoing cognitive neurorobotics studies to contribute to scientific explanation of cognitive phenomena including the senses of minimal and narrative self.

Tonkens (Mind Mach, 19, 3, 421–438, 2009) has issued a seemingly impossible challenge, to articulate a comprehensive ethical framework within which artificial moral agents (AMAs) satisfy a Kantian inspired recipe—"rational" and "free"—while also satisfying perceived prerogatives of machine ethicists to facilitate the creation of AMAs that are perfectly and not merely reliably ethical. Challenges for machine ethicists have also been presented by Anthony Beavers and Wendell Wallach. Beavers pushes for the reinvention of traditional ethics to avoid "ethical nihilism" due to the reduction of morality to mechanical causation. Wallach pushes for redoubled efforts toward a comprehensive account of ethics to guide machine ethicists on the issue of artificial moral agency. Options, thus, present themselves: reinterpret traditional ethics in a way that affords a comprehensive account of moral agency inclusive of both artificial and natural agents, or give up on the possibility and “muddle through” regardless. This series of papers pursues the first option, meets Tonkens' "challenge" and pursues Wallach's ends through Beavers’ proposed means, by "landscaping" traditional moral theory in resolution of a comprehensive account of moral agency. This first paper sets out the challenge and establishes the tradition that Kant had inherited from Aristotle, briefly entertains an Aristotelian AMA, fields objections, and ends with unanswered questions. The next paper in this series responds to the challenge in Kantian terms, and argues that a Kantian AMA is not only a possibility for Machine ethics research, but a necessary one.

ContextHypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality.ObjectiveThe objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1–24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day.DesignA double-blind, placebo-controlled, random-order, cross-over study was conducted.SettingThis study took place in a clinical research center.ParticipantsParticipants included healthy men and women.InterventionsInterventions included an intravenous infusion of cosyntropin (70 μg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo.Main Outcome MeasuresOutcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions.ResultsCosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ± 1.38 vs 17.0 ± 2.07; during 14.4 ± 1.43 vs 17.3 ± 1.65; and next day 14.8 ± 1.42 vs 18.9 ± 2.04; P ConclusionsACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

Background Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. Methods Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients’ clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. Results Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. Conclusion Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.

Despite the frequency of hypospadias (1: 125 live male births) often the etiology is not known. The Lamb Laboratory previously determined that RNA Binding Fox-1 Homolog 2 (RBFOX2) copy number variation (CNV) is associated with clinical cases of upper and lower tract genitourinary (GU) anomalies, including hypospadias. RBFOX2 encodes a RNA binding protein that regulates mRNA splicing. The hypothesis was tested that altered RBFOX2 gene dosage impacts the developing penis transcriptome via mRNA splicing, specifically the mesenchymal to epithelial transition critical for penile urethra formation, resulting in hypospadias.Searches, in publically available and local clinical databases, centered on hypospadias occurance with gene CNV: identified the RBFOX2 locus as a gene dosage sensitve region. To identify developmental pathways regulated by RBFOX2 in the GU system, Rbfox2 haploinsufficient and null mouse models were developed, and penises were collected for RNA-seq, in situ hybridization, and micro-CT analysis of urethral development. In situ hybridization together with re-analysis of published scRNA-seq datasets were employed to define the anatomical regions of Rbfox2-specific expression in the developing mouse penis [Amato & Yao, PNAS 118(25): e2103856118, 2021; Armfield & Cohn, Dev Biol 477: 145-154.2021].Publicly available clinical data identified 17 patients (0.068% n=24,896) with pathogenic RBFOX2 CNVs: 4 were noted to have hypospadias. Results from our cohort of non-syndromic GU birth defect patient samples identified 11 patients (2.4% n=450) with RBFOX2 CNVs: 21% of whom have hypospadias. RNA immunoprecipitation agianst RBFOX2 in human kidney cells validated mRNA transcipt targets previously identified in cardiac cells [Verma 2016]. Micro-CT analysis on fetal Rbfox2-haploinsufficient mice validated the modeled clinical phenotype. Combined in situhybridization and scRNA-seq spatial analysis on mouse samples revealed, after penile sex determination (E15.5), Rbfox2 expression becomes restricted to the penile urethral mesenchyme. Differential gene expression and transcript usage analysis on the Rbfox2-loss mouse penis transcriptome identified mis-expression of gene products associated the estrogen signalling pathway.Alterations in RBFOX2 gene dosage clinically correlate with upper and lower tract genitourinary anomalies, specifically hypospadias. Data from human cell lines and mouse models seemingly indicate the phenotype seems is partially the product of an RBFOX2 role in directing the mesenchymal to epithelial transition. Specifically our data support the a direct role of RBFOX2 in balancing the competing male and female pathways at the level of estrogen and androgen signaling pathways. We are currently using immunofluorescence experiments to define the changes in androgen-receptor, estrogen-receptor, and RBFOX2 patterning throughout perinatal penis development. Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.

Among the proxy traits involved in the adaptive response of wheat to drought and other abiotic stresses, information on the QTLome governing osmotic adjustment (OA) and chlorophyll fluorescence imaging (CFI) is very limited, mainly due to the difficulty to measure these traits on a scale suitable for GWAS. In this study, OA and CFI were measured in plots of 248 elite accessions of durum wheat grown (two replicates) under a fully automated Lemnatec Field Scanalyzer (LFS) and exposed to a progressively severe drought treatment starting 5 days prior to flowering which lasted for two weeks. Leaf relative water content (RWC), chlorophyll content (SPAD) and leaf rolling (LR) were also measured. CFI was measured (i) in the dark in four time series using the LFS camera and (ii) during daytime using a light-induced fluorescence transient (LIFT) sensor mounted on a manually pushed cart. The high variability in OA and CFI among the durum accessions resulted in high to medium repeatability (h2 = 72.3 and 54.6%, respectively). At the end of the drought treatment (mean leaf RWC = 62.1%), OA and leaf RWC were positively correlated (r = 0.78). Association mapping using flowering time as covariate revealed 15 QTLs for OA (global R2 = 63.6%) as well as eight major QTL hotspots on chromosome arms 1BL, 2BL, 4AL, 5AL, 6AL, 6BL and 7BS where a higher OA capacity was always positively associated with leaf RWC, SPAD and negatively associated with LR, hence indicating a beneficial effect of OA on the water status of the plant. Additionally, the comparative analysis with previous field trials showed concurrent effects for five of these hotspots on normalized difference vegetation index (NDVI), thousand kernel weight (TKW) and/or grain yield (GY), hence supporting OA as a valuable proxy for marker-assisted selection aimed at enhancing drought resistance in wheat.

This paper proposes that existing computational modeling research programs may be combined into platforms for the information of public policy. The main idea is that computational models at select levels of organization may be integrated in natural terms describing biological cognition, thereby normalizing a platform for predictive simulations able to account for both human and environmental costs associated with different action plans and institutional arrangements over short and long time spans while minimizing computational requirements. Building from established research programs, the proposal aims to take advantage of current momentum in the direction of the integration of the cognitive with social and natural sciences, reduce start-up costs and increase speed of development. These are all important upshots given rising unease over the potential for AI and related technologies to shape the world going forward.

Metastatic triple negative breast cancer (TNBC) includes poor prognoses and limited effective therapies. Metastasis is the major barrier to durable clinical responses as many patients appear cured of their disease, yet return to clinic with recurrences from dormant micro-metastases. Immune activating agents, such as Interleukin 12 (IL-12) have attracted attention as anti-cancer adjuvants due to their ability to elicit systemic anti-cancer immunity. Although targeting distributed metastases can be accomplished by intravenous (IV) administration, administration of IL-12 into patient vasculature is highly inefficient due to its short half-life and poor toxicity profile. There is a major unmet need to develop biocompatible carriers that improve targeted delivery of IL-12 by specifically homing to metastatic lesions. Mesenchymal stem cells (MSCs) are considered ideal biodelivery vehicles as they display innate tumor-trophism and can deliver biomolecules specifically to systemic metastases. However, major issues need to be addressed before MSCs can be used to deliver IL-12 to patients: MSC tumor homing needs to be improved, and unmodified MSCs can engraft and contribute to tumor growth and metastasis, raising legitimate safety concerns. To address these major limitations, our laboratory developed a MSC-derived biodelivery vehicle with enhanced homing abilities to deliver biomolecules directly to tumors. Our approach involved using scRNA-seq to identify chemoattractant receptor/ligand pairs (CXCR4/CXCL12, CCR2/CCL2) and endothelial adhesion molecules (PSGL-1/P-E-Selectins) that mediate leukocyte homing and extravasation. We then lentivirally expressed these receptors in MSCs and removed nuclei using Ficoll gradient ultracentrifugation. These bioengineered enucleated MSCs (termed Cargocytes™) have a defined lifespan (4 days) and robustly home to TNBC. This is an important breakthrough as TNBC-trophic Cargocytes can be scaled for clinical applications and are safe for in vivo use as described in our recent publication (Nature Biomedical Engineering, in press). By using syngeneic mouse models of metastatic TNBC, we have observed IV-injected Cargocytes robustly extravasate and precisely home to metastatic lung nodules, suggesting Cargocytes act as remarkable biodelivery vehicles. Indeed, the tumor-trophism of Cargocytes includes both integrating into large macro-metastases and homing to broadly distributed micro-metastases. Cargocytes effectively produce and deliver high doses of IL-12 to mouse TNBC, which induces strong immune activation in tumors. This immune activation involved a potent anti-metastatic response, evidencing strong therapeutic efficacy. These findings suggest Cargocyte-delivered IL-12 could constitute a safe, potent, and highly specific anti-metastatic therapy for TNBC and other metastatic cancers sharing similar chemoattractant profiles. Citation Format: Jeffrey White, Huawei Wang, Flavia Franco Da Cunha, Maureen Ruchhoeft, Richard Klemke. Bioengineering enucleated cell vehicles for targeted delivery of Interleukin 12 to metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3519.

Metastatic triple negative breast cancer (TNBC) includes poor prognoses and limited effective therapies. The prevalence of systemic micro-metastases is a major barrier to achieving durable clinical outcomes. Oncolytic viruses (OVs) have garnered attention as anti-cancer adjuvants due to their potential for systemic delivery and ability to lyse tumor cells while leaving healthy cells unaffected. Clinical trials have been conducted testing the efficacy of OVs on diverse cancers. Although targeting distributed metastases can be accomplished by intravenous (IV) administration, administration of virus into patient vasculature is inefficient due to the clearance of unprotected viruses by host immunity. There is a major unmet need to develop biocompatible carriers that improve delivery of OVs by circumventing host anti-viral immunity while homing to metastatic lesions. Mesenchymal stem cells (MSCs) are ideal OV carriers as they display innate tumor-trophic properties, propagate OVs, and shield virions from immunity until reaching their target. However, issues need to be addressed before MSCs can deliver OVs to patients: tumor homing needs improved and unmodified MSCs can engraft and contribute to tumor growth and metastasis, raising safety concerns. To address these limitations, our laboratory developed a MSC-derived biodelivery vehicle with enhanced homing abilities to deliver biologics, such as OVs, directly to tumors. Our approach involved using scRNA-seq to identify chemoattractant receptor/ligand pairs (CXCR4/CXCL12, CCR2/CCL2) and endothelial adhesion molecules (PSGL-1/P-E-Selectins) that mediate leukocyte tumor homing and extravasation. We then lentivirally expressed these receptors in MSCs and removed all DNA using ultracentrifugation and Ficoll density gradients. These bioengineered enucleated MSCs (Cargocytes™) have a defined lifespan (4 days) and robustly home to TNBC. This is an important breakthrough as TNBC-trophic Cargocytes can be scaled for clinical applications and are safe for in vivo use as described in our recent publication (Nature Biomedical Engineering, in press). OVs replicate in and lyse interferon-deficient tumor cells while having negligible effects on healthy cells. As the interferon response is absent in enucleated cells, Cargocytes support robust replication of OVs, including oncolytic Herpes Simplex Virus, Measles Virus, and Vesicular Stomatitis Virus (oVSV), allowing IV delivery of high titer OVs to tumors. In in vivo mouse models of metastatic TNBC, carrier-free oVSV fails to infect lung metastases. However, Cargocytes efficiently deliver oVSV to distributed micro-metastases and integrate deep into macro-metastases, evidencing a remarkable improvement in tissue distribution over intra-tumoral injections. Our findings suggest Cargocytes host and target oVSV directly to TNBC, constituting a highly specific OV delivery vehicle. Citation Format: Jeffrey White, Huawei Wang, Flavia Franco Da Cunha, Maureen Ruchhoeft, Richard Klemke. Bioengineering enucleated cell vehicles for tumor targeted intravenous delivery of oncolytic viruses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 378.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Failure to recognize symptoms of orthostatic hypotension (OH) may result in falls, syncope, and injuries. The relationship between orthostatic changes in blood pressure and symptom occurrence and severity is not known. The goal of the present study was to define the relationship between the occurrence and severity of the symptoms of orthostatic hypotension (OH) and (1) the upright systolic blood pressure (SBP) and (2) the fall in SBP after tilting in patients with OH. We prospectively studied 89 patients with OH. Reported BP values include the lowest BP in the first 3 minutes of tilt and the change in blood pressure during tilt. Subjects were queried about symptoms of orthostatic intolerance while supine and during the first 3 minutes of tilt testing using Question 1 of the Orthostatic Hypotension Questionnaire. Mean tilted SBP was 101.6±26.1 mm Hg and mean SBP fall 47.9±18.1 mm Hg. Mean symptom scores when upright were: light-headedness (2.3/10±2.7), dizziness (1.6/10±2.5), and impending blackout (0.8/10±1.9). The majority of patients were asymptomatic or mildly symptomatic and no discrete cutoff for symptoms was observed. The magnitude of the SBP fall ( r =−0.07, P =NS) and the lowest upright SBP ( r =0.08, P =NS) did not correlate with any reported symptom. These results suggest a poor relationship between the magnitude of the orthostatic BP fall, the upright orthostatic BP, and symptoms. Many patients are asymptomatic despite substantial SBP falls and low orthostatic blood pressures. These findings have implications for clinical care of patients with OH and clinical trials to treat patients with OH.

From his preliminary analysis in 1965, Hubert Dreyfus projected a future much different than those with which his contemporaries were practically concerned, tempering their optimism in realizing something like human intelligence through conventional methods. At that time, he advised that there was nothing “directly” to be done toward machines with human-like intelligence, and that practical research should aim at a symbiosis between human beings and computers with computers doing what they do best, processing discrete symbols in formally structured problem domains. Fast-forward five decades, and his emphasis on the difference between two essential modes of processing, the unconscious yet purposeful mode fundamental to situated human cognition, and the “minded” sense of conscious processing characterizing symbolic reasoning that seems to lend itself to explicit programming, continues into the famous Dreyfus–McDowell debate. The present memorial reviews Dreyfus’ early projections, asking if the fears that punctuate current popular commentary on AI are warranted, and in light of these if he would deliver similar practical advice to researchers today.

Case: We describe the use of local antibiotics to salvage an infected below-knee amputation in a diabetic patient and prevent the need to convert to the above-knee level. After débridement, an antibiotic tibial “dowel” was fashioned and inserted into the intramedullary canal before closure. The wound was fully healed after four months, and the patient remained satisfied at 15 months. Conclusion: This case report offers an adjunct to the conventional management of diabetic stump infections. The addition of an antibiotic spacer could offer an alternative to a higher level of amputation and improve the survival rates of below-knee amputation in this difficult population.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories���DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis���with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy. Profiling multi-platform genomics of 110 cancer patients with an exceptional therapeutic response, Wheeler et al. identify putative molecular mechanisms explaining this survival phenotype in ���23% of cases. Therapeutic success is related to rare molecular features of responding tumors, exploiting synthetic lethality and oncogene addiction.

Nick Bostrom's recently patched "simulation argument" (Bostrom in Philos Q 53:243---255, 2003; Bostrom and Kulczycki in Analysis 71:54---61, 2011) purports to demonstrate the probability that we "live" now in an "ancestor simulation"--that is as a simulation of a period prior to that in which a civilization more advanced than our own--"post-human"--becomes able to simulate such a state of affairs as ours. As such simulations under consideration resemble "brains in vats" (BIVs) and may appear open to similar objections, the paper begins by reviewing objections to BIV-type proposals, specifically those due a presumed mad envatter. In counter example, we explore the motivating rationale behind current work in the development of psychologically realistic social simulations. Further concerns about rendering human cognition in a computational medium are confronted through review of current dynamic systems models of cognitive agency. In these models, aspects of the human condition are reproduced that may in other forms be considered incomputable, i.e., political voice, predictive planning, and consciousness. The paper then argues that simulations afford a unique potential to secure a post-human future, and may be necessary for a pre-post-human civilization like our own to achieve and to maintain a post-human situation. Long-standing philosophical interest in tools of this nature for Aristotle's "statesman" and more recently for E.O. Wilson in the 1990s is observed. Self-extinction-level threats from State and individual levels of organization are compared, and a likely dependence on large-scale psychologically realistic simulations to get past self-extinction-level threats is projected. In the end, Bostrom's basic argument for the conviction that we exist now in a simulation is reaffirmed.

Background:Background: Osteoporosis is a common condition and the economic burden of osteoporosis-related fractures is significant. While studies have reported the incremental or attributable costs of osteoporosis-related fracture, data on the economic impact of osteoporosis-related fractures in commercial health plan populations are limited. Abstract: Objective:Objective: To estimate the direct costs of osteoporosis-related fractures among pharmacologically treated patients in a large, commercially insured population between 2005 and 2008. Abstract: Methods:Methods: In this retrospective cohort study, patients were identified from a large, commercially insured population with integrated pharmacy and medical claims. Inclusion criteria were age 45-64 years; one or more osteoporosis medication claim(s) with first (index) claim between 1 January 2005 and 30 April 2008; and continuous insurance coverage for ≥12 months pre-index and ≥6 months post-index. Patients with pre-index Paget's disease or malignant neoplasm; skilled nursing facility stay; combination therapy at index; or fracture ≤6 months post-index were excluded. A generalized linear model compared differences in 6-month pre-/post-event costs for patients with and without fracture. Propensity score weighting was used to ensure comparability of fracture and non-fracture patients. Generalized estimating equations accounted for repeated measures. Abstract: Results:Results: The study included 49 680 patients (2613 with fracture) with a mean (SD) age of 56.4 (4.7) years; 95.9% were female. Mean differences between pre- and post-event direct costs were &dollar;US14 049 (95% CI 7670, 20 428) for patients with vertebral fractures, &dollar;US16 663 (95% CI 11 690, 21 636) for patients with hip fractures, and &dollar;US7582 (95% CI 6532, 8632) for patients with other fractures. After adjusting for covariates, osteoporosis-related fractures were associated with an additional &dollar;US9996 (95% CI 8838, 11 154; p < 0.0001) in direct costs per patient across all fracture types during the 6 months following fracture. Abstract: Conclusion:Conclusion: Patients with osteoporosis-related fractures were found to incur nearly &dollar;US10 000 in estimated additional direct healthcare costs in the 6 months post-fracture, compared with patients with no fracture. Reduced fracture risk may lower associated direct healthcare costs.

The association between bisphosphonate adherence in the first 12 months after therapy initiation and subsequent fracture risk was examined. Patients were identified from a large, commercially-insured population with integrated pharmacy and medical claims. Eligible patients were aged ≥45 years, were new to osteoporosis therapy (no osteoporosis medication claims in prior year) with first (index) bisphosphonate claim between 1/1/2005 and 4/30/2008, and had continuous insurance coverage for ≥12 months pre- and post-index. Patients with fracture claims ≤12-months post-index were excluded. Adherence was assessed using the medication possession ratio (MPR) over 12-months post-index (i.e., sum of days' supply dispensed divided by 365 days). Patients with a MPR0.8 were considered adherent. The follow-up period to assess incident fracture began at month 13. The analysis included 33,558 new bisphosphonate users with mean age (SD) 59.5 (9.3) years; 94.0% were female. Median MPR at 12 months was 0.61 for alendronate and risedronate; 0.58 for ibandronate. Proportionally more nonfracture patients (39.3%) had a MPR0.8 compared with fracture patients (34.9%, p0.001). In multivariate modeling of bisphosphonate users' experience, those with a MPR0.8 had a 14% lower risk of subsequent fracture than those with MPR0.5, after controlling for demographics, insurance type, select comorbidities, and other potential confounders (p=0.0459). In a large, commercially-insured population, suboptimal adherence with bisphosphonate treatment was associated with increased fracture risk even after controlling for potential confounders.

The Los Angeles Unified School District (LAUSD) serves a large majority of socioeconomically disadvantaged students who are struggling academically and are underprepared for high school graduation and college. This article describes the partnership between LAUSD and the Los Angeles Education Research Institute, and how this collaboration endeavors to produce accessible and high-quality research to inform pressing problems of practice. The article also presents findings from an ongoing partnership research project analyzing a district policy focused on improving college readiness by aligning high school graduation and college-eligibility requirements. In a cohort that went through high school before the policy became mandatory for all students, less than 1/5 of all students (and 30% of graduates) met the college eligibility criteria. Our findings indicate that academic and behavioral indicators from 8th and 9th grade can help identify for possible intervention students who are not on track to meet these new graduation requirements.

This paper reviews the complex, overlapping ideas of two prominent Italian philosophers, Lorenzo Magnani and Luciano Floridi, with the aim of facilitating the nonviolent transformation of self and world, and with a focus on information technologies in mediating this process. In Floridi’s information ethics, problems of consistency arise between self-poiesis, anagnorisis, entropy, evil, and the narrative structure of the world. Solutions come from Magnani’s work in distributed morality, moral mediators, moral bubbles and moral disengagement. Finally, two examples of information technology, one ancient and one new, a Socratic narrative and an information processing model of moral cognition, are offered as mediators for the nonviolent transformation of self and world respectively, while avoiding the tragic requirements inherent in Floridi’s proposal.

International audience; Terahertz Time Domain Imaging has been used in the last few years for the investigation of cultural heritage. In this article, the authors demonstrate the possibility to apply it for the investigation of clay artifacts. Tomographic images were obtained of a model in reflection, and an Egyptian vessel in transmission. © 2011 Springer-Verlag.

Bed bugs, Cimex lectularius L., are now considered a serious urban pest in the United States. Because they are small and difficult to find, there has been strong interest in developing and using monitoring tools to detect bed bugs and evaluate the results of bed bug control efforts. Several bed bug monitoring devices were developed recently, but their effectiveness is unknown. We comparatively evaluated three active monitors that contain attractants: CDC3000, NightWatch, and a home-made dry ice trap. The Climbup Insect Interceptor, a passive monitor (without attractants), was used for estimating the bed bug numbers before and after placing active monitors. The results of the Interceptors also were compared with the results of the active monitors. In occupied apartments, the relative effectiveness of the active monitors was: dry ice trap > CDC3000 > NightWatch. In lightly infested apartments, the Interceptor (operated for 7 d) trapped similar number of bed bugs as the dry ice trap (operated for 1 d) and trapped more bed bugs than CDC3000 and NightWatch (operated for 1 d). The Interceptor was also more effective than visual inspections in detecting the presence of small numbers of bed bugs. CDC3000 and the dry ice trap operated for 1 d were equally as effective as the visual inspections for detecting very low level of infestations, whereas 1-d deployment of NightWatch detected significantly lower number of infestations compared with visual inspections. NightWatch was designed to be able to operate for several consecutive nights. When operated for four nights, NightWatch trapped similar number of bed bugs as the Interceptors operated for 10 d after deployment of NightWatch. We conclude these monitors are effective tools in detecting early bed bug infestations and evaluating the results of bed bug control programs.

CHAS W. FREEMAN, JR.: (Off mike) used to a podium, but we will make this presentation sitting down. And it is about 9:30 Arab standard time and I will it's my pleasure to welcome everyone here. I'm Chas Freeman. I have the honor to be president of the Middle East Policy Council. And we will proceed I'll make a few remarks and then we'll proceed directly to discussion of "Occupied Iraq: One Country, Many Wars."

Objective: To assess the relationship between diabetic medication adherence, total healthcare costs, and utilization within patients with type 2 diabetes mellitus and concomitant diabetes and cardiovascular disease (CVD). Research design and methods: This study was a retrospective analysis of pharmacy and medical claims from 1 April 1998 through 31 March 2000 within a managed care organization’s database. Patients were identified who had received an oral antihyperglycemic medication or had a diagnosis of CVD, were continuously enrolled in the health plan, and were ≥30 years of age. The likelihood of an emergency room (ER) or hospital admission and total healthcare costs related to all causes, stratified by antihyperglycemic medication adherence cohort within the diabetes only and diabetes + CVD groups, were examined over 360 days from the date the patient was identified. Results: For diabetes patients with ≤75, >75 to ≤95, and >95% adherence, adjusted total healthcare costs (from April 1998 to March 2000) were $US5706, $US5314, and $US4835, respectively (p 75 to ≤95% adherence had a 31% and 19% greater chance of a hospital/ER admission than those in the >95% cohort, respectively. Adjusted healthcare costs (from April 1998 to March 2000) for those with ≤75, >75 to ≤95, and >95% adherence within the diabetes + CVD cohort was $US37 648, $US31 547, and $US25 354 (p 75 to ≤95% adherent had a 44% and 51% greater chance of a hospital/ER admission than those with >95% adherence, respectively. Conclusions: Higher adherence to oral antihyperglycemic agents is associated with lower healthcare resource utilization and costs for patients with diabetes only and patients with concomitant diabetes and CVD.

This is an article showing how our organization has begun to implement safety training into our medical training to intervene in human nature and make our crews and patients safer.

Design: Retrospective database analysis using pharmacy and medical claims from a pharmacy benefit and medical management company serving a large managed care organization (MCO) that provides healthcare coverage for approximately 3.5 million members. Participants: Patient selection was based on the following criteria: (i) newly started on antidepressant therapy between 1 April 1999 through 30 June 1999; (ii) titrated to a usual antidepressant dosage level within 6 months of the initiation of therapy; (iii) continuously enrolled in the health plan between 1 January 1999 through 31 December 1999; and (iv) >18 years of age. Outcome measures: Antidepressant adherence was calculated as a ratio of the total number of day’s supply during the 180-day follow-up period divided by 180 days. Patients were defined as adhering to treatment if they had a ratio of ≥0.70. The means of pharmacy ingredient costs, medical charges and total healthcare charges incurred during the follow-up period were compared. Adjusted means (least squares means) were calculated after adjusting for potential confounding factors that may have influenced relevant outcomes. Results: Of the total cohort (14 190 patients), 39.7% (n = 5638) of patients were deemed to be adhering (≥70.0% completion) to their treatment. Adherent patients were significantly more advanced in age (55.2 vs 54.3 years, p < 0.01) and had a higher mean Chronic Disease Score (3.80 vs 3.47, p < 0.0001). After adjusting for confounding factors, adherent patients incurred lower total healthcare charges ($US11 327 vs $US11 815, p = 0.433) significantly lower medical charges ($US9411 vs $US10 692, p = 0.039) and significantly higher pharmacy charges ($US1915 vs $US1123, p < 0.0001) than non-adherent patients during the initial 6 months of therapy (all 1999 values). Conclusion: In this MCO, patients who were adherent with antidepressant therapy possessed significantly lower medical charges. These findings indicate that patient adherence with antidepressant therapy significantly improved the economic outcomes. It is suggested that there is a need for raising awareness about the importance of patient adherence as well as to improve methods of detecting individuals with depression in order to gain the economic benefits associated with adherence. Depressive disorders are common in the general population of disorders in a large sample of 20 000 people. [2] The study revealed Western societies, with a prevalence of about 2–4% for major that medically ill patients had a 41% higher prevalence rate of a depression and an approximate 20% lifetime risk for the develop- psychiatric illness and a 28% higher prevalence of a lifetime ment of major depression in the US. [1] Several studies have evalu- psychiatric disorder compared with the matched control healthy ated the comorbidity of depression and various medical condi- population. Luber et al. [3] evaluated the relationship between cotions. The National Institute of Mental Health Epidemiological morbidity and depression in a group of patients who were seen at a Catchment Area study analyzed the prevalence of psychiatric general internal medicine practice. The study showed that de

METHODS: This study was a retrospective database analysis of pharmacy and medical claims for 14,826 commercial (40.9%) and Medicare+Choice (59.1%) members of a large HMO in California who were newly started on HMG therapy during the identification period, continuously enrolled during the review period (defined as each member’s 6-month pre-index period through 360 days of follow-up), and between 18 and 75 years of age. Members who exclusively used only the mail-service pharmacy for HMG prescriptions were compared to members who used only community pharmacies for HMG prescriptions. The main outcome measures were adherence, medication possession ratio (MPR), persistence, prescription count, and duration of therapy. RESULTS: All outcome measures were significantly greater for the mail-service cohort than for the community pharmacy cohort (p

This paper is about modeling morality, with a proposal as to the best way to do it. There is the small problem, however, in continuing disagreements over what morality actually is, and so what is worth modeling. This paper resolves this problem around an understanding of the purpose of a moral model, and from this purpose approaches the best way to model morality.

Background: Dronedarone is a non-iodinated form of amiodarone that may not cause some of serious adverse effects associated with amiodarone. However, it is less effective than amiodarone in maintaining normal sinus rhythm, and it does not improve success of electrical cardioversion. Additionally, dronedarone use has been associated with new onset or worsening of heart failure (HF), including a doubling of the risk of death in patients with symptomatic heart failure. We aimed to compare the incidence of newly diagnosed HF and HF hospitalizations among dronedarone and amiodarone users. Secondary outcomes of interest included rates of acute ischemic stroke (IS) and transient ischemic attack (TIA). Methods: This retrospective study utilized administrative claims data between 1/1/2007-9/30/2011 from the HealthCore Integrated Research Environment (HIRE ® ). Patients were required to have at least one claim for atrial fibrillation. Propensity score matching was employed to adjust for differences between the cohorts. Incidence rate of HF, HF hospitalizations, IS and TIA events were compared between matched cohorts using Poisson time-to-event model. Results: The cohort consisted of 6,013 amiodarone and 1,534 dronedarone patients. Dronedarone patients were younger, healthier per Deyo-Charlson Index (DCI) and CHADS2 score, and less likely to have underlying heart disease (all p-values Conclusions: In a propensity score matched observational cohort study, amiodarone use was associated with higher incidence rate of new onset HF, HF hospitalizations, and TIA as identified from claims. This finding differs from other clinical studies. Future observational cohort studies should incorporate medical record review for validation since information from claims might be insufficient to fully account for underlying patient risk status, or accurately determine if HF was new onset. Key words: amiodarone; dronedarone; atrial fibrillation; heart failure.

We assessed the potential of pheromone-mediated mating disruption to control the black headed fire worm of cranberries, Rhopobota naevana (Hubner). In experimental plots (30 by 30 m) on cranberry farms, spiral polyvinyl chloride pheromone dispensers released either the main component of fire worm pheromone, (Z)-ll-tetradecen-l-ol acetate, or a 3-component blend, (Z)-ll-tetradecen-l-ol acetate, (Z)-ll-tetradecen-l-ol, and (Z)-9-dodccen-1-ol acetate, which is similar to the natural pheromone. In both years of the study, the incidence of mating of laboratory-reared female moths placed in pheromone-treated plots was reduced relative to those placed in control plots. Release rates of pheromone, which were estimated from the curvilinear relationship between the amount remaining in dispensers and time in the field, declined linearly and slowly over the experimental period. The estimated release ratio of the 3-component blend decreased from 5.2:1.9:1.0 at the beginning of the Season to 1.9:1.1:1.0 at the end. Results suggest that mating disruption is a promising technique for Immagement of the black headed fire worm.

Antibody microarrays permit sensitive and semi-quantitative analysis of the expression, covalent modification and interactions of proteins in lysates of cells and tissues. At Kinexus, we have developed high content Kinex KAM microarrays that feature nearly 900 pan- and phosphosite-specific antibodies for monitoring protein kinases, phosphatases and other low abundance cell signalling proteins with combinations of different detection systems. One method involved capture of in vitro dye-labeled proteins (e.g. with Cy3) from lysates from cells subjected to diverse treatments. Another method involved the detection of changes in their total phosphorylation with biotinylated pIMAGO stain and an anti-biotin antibody that is labeled with a different dye (e.g. Cy5). Alteration in protein-tyrosine phosphorylation were monitored with a dye-labelled, generic phosphotyrosine-specific PYK antibody in a sandwich antibody microarray (SAM) format. The SAM technique was also used to explore the interactions of adapter, scaffolding and chaperone proteins with hundreds of potential target signal transduction proteins with dye-labeled reporter antibodies for these highly interactive proteins. We used several human cancer cell lines (e.g. A431, HeLa, Jurkat, MCF7) subjected to diverse treatments (e.g. growth factors) to identify biomarkers for the actions of these agents. Reproducible results were obtained with as little as 25 μg of lysate protein, with a dynamic range of detection exceeding 6000-fold, and a median error range for duplicates measurements of ±12%. Typically 10-15% of the proteins tracked with these arrays demonstrated perturbations exceeding 50%. More than a third of the leads from our antibody microarrays were confirmed by immunoblotting studies. The major limitation associated with validation by Western blotting was the much lower sensitivity with immunoblotting compared with antibody microarrays. We also explored the specific interactions of heat shock proteins, adapter proteins, 14-3-3 and calcium-binding proteins with the antibody microarray captured lysate proteins from cancer cell lines. By combining these detection strategies, it was feasible to obtain over 7000 data points from use of a single antibody microarray slide with two lysate samples and duplicate measurements. The goal of our proteomics and bioinformatics studies is to use the experimental results from the application of these microarrays to map the architecture of signalling networks in a cell- or tissue-specific manner. Such multi-tiered microarray-based analyses permit target-directed identification of diverse regulatory protein changes in different experimental model systems with greater sensitivity, breadth, selectivity and economy when compared to any other competing proteomics methodologies. Citation Format: Steven Pelech, Lambert Yue, Jeffrey White, Ryan Hounjet, Dirk Winkler. Profiling signalling protein expression, modifications and interactions with multi-dimensional antibody microarrays. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4552.

BACKGROUND: Despite widespread availability and use of oral bisphosphonates, fracture rates and associated medical costs are still high. Differences in fracture risk among these agents, if any, have not been quantified due to the lack of high-quality, head-to-head, randomized, controlled trials assessing this outcome. Randomized, placebo-controlled trials have shown that alendronate and risedronate reduce rates of both vertebral and nonvertebral fractures, whereas only reduction in vertebral fractures has been found for ibandronate. OBJECTIVE: To determine if there were any differences among 3 oral bisphosphonates in adherence, total cost of care, and effectiveness in reducing fracture rates in a large managed care population. METHODS: Administrative, longitudinal pharmacy and medical claims data were obtained from 14 geographically diverse health plans in the United States covering approximately 14 million members. Sampled members had at least 1 pharmacy claim for alendronate, risedronate, or ibandronate during the intake period (January 1, 2005, through October 31, 2007). The date of the first pharmacy claim for osteoporosis medications within the intake period was the index date. Members were followed for either 12, 24, or 36 months, depending on length of continuous health plan eligibility. Medication possession ratio (MPR) was measured using a total days supply that was calculated by multiplying the total quantity dispensed by the suggested days supply per unit of dispensing based on manufacturer-recommended dosing. For members who switched bisphosphonate strengths or medications, the estimated days supply was summed for all osteoporosis medications during the follow-up, including overlapping days supply. Outcomes included (a) the first incident fracture and percentages of members with at least 1 fracture after 6 months post-index; (b) the number of days from index to the first incident fracture, measured as time to event in Cox proportional hazards regression analysis; and (c) total all-cause health care costs (health plan allowed amount including member cost share). RESULTS: A total of 45,939 members were included (n = 24,909 alendronate, n = 13,834 risedronate, n = 7,196 ibandronate). In the 12-month analysis, MPRs were comparable (means = 0.57-0.58) for the 3 medications. After 24 months, MPRs had dropped for all medications, but those of both alendronate (mean = 0.50, 95% CI = 0.49-0.50) and risedronate (mean = 0.50, 95% CI = 0.49-0.51) were slightly higher than that of ibandronate (mean = 0.47, 95% CI = 0.46-0.48). At 36 months, again the MPRs had dropped for all 3 medications (means = 0.44-0.47) but were similar. There were no statistically significant differences among agents in the percentages of subjects with at least 1 fracture at 12, 24, or 36 months (36-month rates: alendronate 4.41%, risedronate 4.38%, ibandronate 6.28%, P = 0.102). The numbers of subjects with fracture(s) per month of follow-up were 0.0020 for alendronate, 0.0021 for risedronate, and 0.0022 for ibandronate (P = 0.087 overall). However, after adjusting for member characteristics, alendronate users had a 12% lower risk of experiencing R ESEAR C H any incident fracture than ibandronate users (hazard ratio = 0.88, 95% CI = 0.78-0.99, P = 0.034) within the follow-up period. In the first 12 postindex months, ibandronate users had higher mean [SD] unadjusted total all-cause health care costs ($7,464 [$15,975]) compared with alendronate ($7,233 [$16,671]) and risedronate ($6,983 [$16,870], P < 0.001 for both comparisons), differences of approximately $19 per month and $40 per month, respectively. The results of the unadjusted 24-month analysis were similar, but there were no significant cost differences at 36 months. Total cost differences for the 3 medication groups were nonsignificant at 12, 24, and 36 months after adjusting for member characteristics. CONCLUSIONS: This retrospective analysis of an administrative claims database in a large managed care population showed similar rates of adherence and total adjusted all-cause health care costs for alendronate, risedronate, and ibandronate. Absolute unadjusted rates of fracture were small and did not significantly differ among agents, but after controlling for differences in member characteristics, the risk of fracture was 12% lower for alendronate users than for ibandronate users.

Prostate cancer continues to represent a burgeoning medical problem in the United States. Recent studies suggest that gossypol, a bioactive phytochemical produced by cotton plants, is a promising agent against prostate cancer. The current studies were undertaken to examine the chemotherapeutic efficacy of gossypol on human prostate cancer cell lines and prostate tumor–initiating cells. Gossypol reduced the viability of three prostate cancer cell lines (LAPC4, PC3, and DU145) with an IC50 between 3 and 5 μmol/L. Additionally, gossypol was effective at inhibiting prostate tumor–initiating cell-driven tumor growth in a nonobese diabetic/severe combined immunodeficient xenograft model. Our integrated molecular profiling approach encompassing proteomics, activated transcription factors, and genomics suggests that the decrease in viability was associated with increased DNA damage and the induction of apoptosis. Exposure of DU145 cells to gossypol (1–10 μmol/L) resulted in the activation of 13 proteins and 7 transcription factors, and the expression of 17 genes involved in the mitochondrial pathway of apoptosis. These studies show for the first time that gossypol treatment induces DNA damage and activates p53. Collectively, these data support the use of gossypol as a novel agent for prostate cancer. Mol Cancer Ther; 9(2); 461–70

Recent developments, both in the cognitive sciences and in world events, bring special emphasis to the study of morality. The cognitive sciences, spanning neurology, psychology, and computational intelligence, offer substantial advances in understanding the origins and purposes of morality. Meanwhile, world events urge the timely synthesis of these insights with traditional accounts that can be easily assimilated and practically employed to augment moral judgment, both to solve current problems and to direct future action. The object of the following paper is to present such a synthesis in the form of a model of moral cognition, the ACTWith model of conscience. The purpose of the model is twofold. One, the ACTWith model is intended to shed light on personal moral dispositions, and to provide a tool for actual human moral agents in the refinement of their moral lives. As such, it relies on the power of personal introspection, bolstered by the careful study of moral exemplars available to all persons in all cultures in the form of literary or religious figures, if not in the form of contemporary peers and especially leadership. Two, the ACTWith model is intended as a minimum architecture for fully functional artificial morality. As such, it is essentially amodal, implementation non-specific and is developed in the form of an information processing control system. There are given as few hard points in this system as necessary for moral function, and these are themselves taken from review of actual human cognitive processes, thereby intentionally capturing as closely as possible what is expected of moral action and reaction by human beings. Only in satisfying these untutored intuitions should an artificial agent ever be properly regarded as moral, at least in the general population of existing moral agents. Thus, the ACTWith model is intended as a guide both for individual moral development and for the development of artificial moral agents as future technology permits.

The results of both a laboratory and factory trial of a time‐domain terahertz (TD‐THz) multi‐layer gauge for on‐line process monitoring are presented. The TD‐THz gauge is demonstrated on a two layer laminated plastic insulation material. The TD‐THz gauge simultaneously measured the total and the individual layer thicknesses. Measurements were made while transversely scanning across a 12 foot wide sheet extruded at high speed in a factory environment. The results were analyzed for precision, accuracy, and repeatability; and demonstrated that the TD‐THz gauge performed in an equivalent or superior manner to existing ionizing radiation gauges (which measure only one layer). Many dielectric materials (e.g., plastic, rubber, paper, paint) are transparent to THz pulses, and the measurement of a wide range of samples is possible.