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Scale-based models of weighing reasons face challenges concerning the context sensitivity of weight, the aggregation of weight, and the methodology for determining what the weights of reasons are. I resolve these challenges.

From the perspective of urban planning, the history of the Town Camps of Mparntwe (Alice Springs) has made them a unique form of urban development within Australia; they embody at once a First Nation form of urbanism and Country, colonial policies of inequity and dispossession, and a disparate public and community infrastructure that reflects the inadequate and ever-changing funding landscape it has been open to. While these issues continue, this paper discusses the resilience of these communities through the Local Decision Making agreement, signed in 2019 between the Northern Territory Government and Tangentyere Council. One thing that has been critical to translating and communicating local decisions for government funding has been the establishment of an inclusive and robust process of participatory mapping—Mapping Local Decisions—where both the deficiencies and potential of community infrastructure within each Town Camp is being identified. As local community knowledge is embedded within these practices, so too are issues of health, accessibility, safety and a changing climate similarly embedded within the architectural and infrastructure projects developed for government funding. Being conceived and supported by local communities, projects are finding better ways to secure this funding, building on a resilience these communities have for the places they live.

Supplemental Methods and Materials. ACF Phospho-ERK and ERK Level Quantification.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.

PDF file - 40K, Effect of Erlotinib (6 mg/kg BW/day) on Time of Appearance of Methylnitrosourea- Induced Mammary Cancers in Female Sprague-Dawley Rats.

PDF file - 50K

Supplementary Materials from Phase IIA Trial Testing Erlotinib as an Intervention against Intraductal Pancreatic Mucinous Neoplasms

Covalent bonding is one of the most robust forms of intramolecular interaction between adhesives and substrates. In contrast to most noncovalent interactions, covalent bonds can significantly enhance both the interfacial strength and durability. To utilize the advantages of covalent bonding, specific chemical reactions are designed to occur at interfaces. However, interfacial reactions are difficult to probe in situ, particularly at the buried interfaces found in well-bonded adhesive joints. In this work, sum frequency generational (SFG) vibrational spectroscopy was used to directly examine and analyze the interfacial chemical reactions and related molecular changes at buried nylon/silicone elastomer interfaces. For self-priming elastomeric silicone adhesives, silane coupling agents have been extensively used as adhesion promoters. Here with SFG, the interfacial chemical reactions between nylon and two alkoxysilane adhesion promoters with varied functionalities (maleic anhydride (MAH) and epoxy) formulated into the silicone were observed and investigated. Evidence of reactions between the organofunctional group of each silane and reactive groups on the polyamide was found at the buried interface between the cured silicone elastomer and nylon. The adhesion strength at the nylon/cured silicone interfaces was substantially enhanced with both silane additives. SFG results elucidated the mechanisms of organo-silane adhesion promotion for silicone at the molecular level. The ability to probe and analyze detailed interfacial reactions at buried nylon/silicone interfaces demonstrated that SFG is a powerful analytical technique to aid the design and optimization of materials with desired interfacial properties.

Many generic anthelmintics are commercially available; however, very little information exists regarding effectiveness of these products compared with pioneer brands. Therefore, the objective of this study was to conduct a fecal egg count reduction test comparing generic eprinomectin (Eprizero) to pioneer eprinomectin (Eprinex), as well as to fenbendazole in grazing beef steers. Naturally infected steers (n = 40; BW = 212±5 kg) were allocated into five treatment groups based on ranked fecal egg counts:. Eprinex (EX), 2. Eprizero (EZ), 3. Safeguard (SG), 4. Eprinex + Safeguard (XS), or 5. Control/No treatment (NT). Fecal samples were collected on days -7, 0, 14, and 29, and body weights were recorded on days -14 and 29. Data were analyzed using the MIXED procedure of SAS 9.4. At day 14 post-treatments, the EX treatment group demonstrated a 50% fecal egg count reduction (FECR), while EZ treatment group had a 79% FECR. Both the SG and XS treatment groups showed a 98% and 100% FECR, respectively. At day 29 post-treatment, EX and EZ treatment groups demonstrated a1% and 5% FECR, while the SG and XS treatment groups displayed a 94% and 89% FECR. The coproculture data indicated that Cooperia punctata, Cooperia oncophora and Ostertagia ostertagi all persisted and comprised at least 90% of the larvae recovered from both the EX and EZ coprocultures performed on days 14 and 29. Haemonchus spp. was recovered from EZ coprocultures on days 14 and 29 (10% and 1%, respectively, of recovered larvae), as well as from the EX coprocultures (4% and%, respectively). Interestingly, the proportions of C. punctata and C. oncophora essentially demonstrated a post-treatment reversal in the both the SG and XS treatment groups when comparing days 0 and 29, possibly indicating a greater efficacy of fenbendazole against than C. punctata. There were no significant differences (P < 0.05) in average daily gains between the treatment groups.

Perceptual dogmatism is a prominent theory in epistemology concerning the relationship between perceptual experience and reasonable belief. It holds that, in the absence of counterevidence, it is reasonable to believe what one’s perceptual experience tells one. Thus, if one is not aware of an experience’s causal history, then it doesn’t matter. Critics object that the causal history does matter: When a perceptual experience is caused in certain ways, it is unreasonable to trust what it tells you. These objections regularly appeal to cognitive penetration and biased searches for evidence. Given the myriad accounts of what covert attention is, one wonders if biased patterns of covert attention could raise a new objection to dogmatism. The author argues that, while covert selection might raise various problems for dogmatism, none of them are new. This is good news for dogmatism because the fewer distinct problems it faces, the more likely it can resolve them all.

Ethicists increasingly reject the scale as a useful metaphor for weighing reasons. Yet they generally retain the metaphor of a reason’s weight. This combination is incoherent. The metaphor of weight entails a very specific scale-based model of weighing reasons, Dual Scale. Justin Snedegar worries that scale-based models of weighing reasons can’t properly weigh reasons against an option. Chapter 4 shows that there are, in fact, two different reasons for/against distinctions, and provides an account of the relationship between the various kinds of reason for and against. With this account in hand, we’ll see that Dual Scale has no problem weighing any kind of reason against.

This paper accomplishes three goals. First, it reveals that God’s ethics has a radical satisficing structure: God can choose a good enough suboptimal option even if there is a best option and no countervailing considerations. Second, it resolves the long-standing worry that there is no account of the good enough that is both principled and demanding enough to be good enough. Third, it vindicates the key ethical assumption in the problem of evil without relying on the contested assumption that God’s ethics is our ethics (on steroids).

Background: Patients on systemic anticoagulation are at increased risk for gastrointestinal bleeding (GIB). Guidelines recommend endoscopy within 24 hours for diagnostic and therapeutic purposes. Unfortunately, lack of resources and/or gastroenterologists in small, community centers limit the ability to perform timely endoscopy. Conservative management is used in this setting with delayed or outpatient endoscopy, specifically in those who respond to medical therapy. There is minimal data on the outcomes of patients managed in this fashion.Objective: To compare outcomes of patients on systemic anticoagulation who present with non-variceal upper GIB in a small community hospital.Design: We conducted a retrospective cohort chart review.Participants: 115 adult patients who met the inclusion criteria for non-variceal upper GIB on systemic anticoagulation. Excluded patients were those on dual antiplatelet therapy, history of decompensated cirrhosis, variceal bleeds, active GIB identified on imaging (defined as contrast extravasation on CT angiogram or positive tagged RBC nuclear scan), and those with gastrointestinal malignancy.Interventions: Resuscitative medical therapy (MT) alone vs inpatient endoscopy with resuscitative MT.Main Measures: Outcomes included red blood cell (RBC) transfusions, re-admission for GIB, and 30-day all-cause mortality. Sub-group analysis was also performed based on endoscopy timeline and anticoagulation type.Key Results: Patient in MT group required less RBC transfusions compared to endoscopy group (1.4 vs 2.5 average units, [95% CI 1.01-1.87]; P=0.004). There was no statistical significance for re-admission for gastrointestinal bleeding or mortality between both groups. Moreover, there was no significant difference in RBC transfusions based on EGD timing. Most patients were on warfarin (n=47) and there were no differences in re-admission for GIB or mortality based on anticoagulant use.Conclusion: Our study suggests that there is no significant therapeutic benefits to inpatient endoscopy in comparison to medical management alone in anticoagulated patients who present with non-variceal UGIB.

An agent submaximizes with motivation when she aims at the best but chooses a less good option because of a countervailing consideration. An agent (radically) satisfices when she rejects the better for the good enough, and does so because the mere good enough gets her what she really wants. Motivated submaximization and satisficing, so construed, are different ways of choosing a suboptimal option, but this difference is easily missed. Putative proponents of satisficing tend to argue only that motivated submaximization can be appropriate while critics of satisficing tend to criticize satisficing, as I construe it. The existing literature, then, leaves (radical) satisficing in a very bad state: there are no good arguments for it and there are three unanswered objections to it. This paper (1) clarifies the distinction between motivated submaximization and satisficing and (2) refutes the three most prominent objections to the claim that satisficing can be appropriate.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.

Pancreatic adenocarcinoma carries a grim prognosis. In 2007, gemcitabine with erlotinib emerged as an appropriate treatment option for patients with advanced inoperable or metastatic disease (APC). In this phase II trial we sought to evaluate the efficacy of erlotinib monotherapy in patients with APC who had disease refractory to or ineligibility for gemcitabine-based therapy. Eligible patients who had received 0 or 1 non-EGFR inhibitor containing gemcitabine-based chemotherapy for APC were recruited prospectively and treated with erlotinib 150 mg orally daily until unacceptable toxicity or disease progression. Primary endpoint was progression-free survival (PFS). Correlations of clinical response with smoking, rash, steady-state concentration of erlotinib and its metabolite (OSI-420) as well as the nicotine metabolite cotinine were performed. The trial was terminated early for futility. Eighteen of the 34 planned subjects were recruited. Median PFS and OS were 42 and 95 days, respectively. Best response was stable disease (21%). There was a trend for improved PFS and OS in never smokers compared to current and past smokers (128.5, 39, 42 days and 173, 100, 88 days, respectively). Past/current smokers had lower steady-state concentrations of erlotinib and OSI-420 compared to never smokers. There was evidence of recent smoking exposure in 30% of patients self-identified as past smokers. Rash was infrequent, with no cases of grade III/IV rash and it was not related to treatment outcomes. Overall, erlotinib monotherapy failed to improve outcomes compared to historical controls in patients with APC after 0–1 prior systemic therapies. There was a trend for improved PFS and OS in never smokers.

We commonly say that some evidence supports a hypothesis or that some premise evidentially supports a conclusion. Both internalists and externalists attempt to analyze this notion of evidential support, and the primary purpose of this paper is to argue that reliabilist and proper functionalist accounts of this relation fail. Since evidential support is one component of inferential justification, the upshot of this failure is that their accounts of inferential justification also fail. In Sect. 2, I clarify the evidential support relation. In Sects. 3–5, I subject reliabilist and proper functionalist accounts of evidential support to various counterexamples. In Sect. 6, I show that the most promising ways to address these counterexamples aren’t very promising.

Perceptual dogmatism holds that if it perceptually seems to S that P, then S thereby has prima facie perceptual justification for P. But suppose Wishful Willy's desire for gold cognitively penetrates his perceptual experience and makes it seem to him that the yellow object is a gold nugget. Intuitively, his desire-penetrated seeming can't provide him with prima facie justification for thinking that the object is gold. If this intuitive response is correct, dogmatists have a problem. But if dogmatists have a problem, you do too (well, most of you anyway). Reliabilists have denounced dogmatism's cognitive penetration problems, but they have problems with cognitive penetration that are even worse.

Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL+VPA and HAL+MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.

Many epistemologists hold that the Zebra Deduction (the animals are zebras, so they aren't cleverly disguised mules) fails to transmit knowledge to its conclusion, but there is little agreement concerning why it has this defect. A natural idea is, roughly, that it fails to transmit because it fails to improve the safety of its conclusion. In his ‘Transmission Failure Explained’, Martin Smith defends a transmission principle which is supposed to underwrite this natural idea. There are two problems with Smith's account. First, Smith's argument for his transmission principle relies on a dubious premise (§1). Second, even if his transmission principle is true, Smith shows neither that it prevents the Zebra Deduction from transmitting knowledge to its conclusion, nor that it secures the natural idea (§2). I suspect that the failures of Smith's account will be instructive for anyone who wants to connect transmission failure with a failure to enhance the safety, reliability or probability of one's conclusion.

Necessity holds that, if a proposition A supports another B, then it must support B. John Greco contends that one can resolve Hume's Problem of Induction only if she rejects Necessity in favor of reliabilism. If Greco's contention is correct, we would have good reason to reject Necessity and endorse reliabilism about inferential justification. Unfortunately, Greco's contention is mistaken. I argue that there is a plausible reply to Hume's Problem that both endorses Necessity and is at least as good as Greco's alternative. Hence, Greco provides a good reason for neither rejecting Necessity nor endorsing inferential reliabilism.

As I use the term, ‘entitlement’ is any warrant one has by default—i.e. without acquiring it. Some philosophers not only affirm the existence of entitlement, but also give it a crucial role in the justification of our perceptual beliefs. These philosophers affirm the Entitlement Thesis: that an essential part of what makes our perceptual beliefs justified is our entitlement to the proposition that I am not a brain-in-a-vat. Crispin Wright, Stewart Cohen and Roger White are among those who endorse this controversial claim. In this paper, I argue that the Entitlement Thesis is false.

Apparently, relationships between God (if He exists) and His creatures would be very valuable. Appreciating this value raises the question of whether it can motivate a certain premise in John Schellenberg's argument from divine hiddenness, a premise which claims, roughly, that if some capable, non-resistant subject fails to believe in God, then God does not exist. In this paper, I argue that the value of divine–creature relationships can justify this premise only if we have reason to believe that the counterfactuals of freedom work out in certain ways. Unfortunately, we can't acquire such a reason, at least not without relying on other successful arguments (if there are any) for the relevant premise of Schellenberg's hiddenness argument.

Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model.Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma).Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated.Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

Galen Strawson has claimed that “the impossibility of free will and ultimate moral responsibility can be proved with complete certainty.” Strawson, I take it, thinks that this conclusion can be established by one argument which he has developed. In this argument, he claims that rational free actions would require an infinite regress of rational choices, which is, of course, impossible for human beings. In my paper, I argue that agent causation theorists need not be worried by Strawson’s argument. For agent causation theorists are able to deny a key principle which drives the regress. Oversimplifying things a bit, the principle states that if one is responsible for her rational actions, then she was antecedently responsible for the reasons on which she acted.

The goal of the City Evolutions Project is to establish interactive systems and games to entertain users. Because of the existing variabilities in the system and potential reuse for similar systems in this domain, the software system is designed and developed in a reuse-based way, i.e. Software Product Line Engineering (SPLE). SPLE is a reuse-based software approach with reusable software assets in order to maximise software reuse. In SPLE, it is very important to maintain the requirement traceability from software family establishment to individual product derivation. In this paper, we describe our experience of applying SPLE approach in the City Evolutions project and propose an approach to enhance the requirements traceability in SPLE.

The seasonal variation of pollen collected from different plant species by greenhouse bumblebees was investigated to determine how frequently bumblebees forage outside of commercial tomato greenhouses. Pollen was collected from bumblebees at three greenhouses between February and September 2001 and the plant species identity of pollen collected was determined with light microscopy. A significant amount of non-tomato pollen was collected by bumblebees during one or more months from outside each of the three greenhouses studied. The bees brought back as little as an average of 5% non-tomato pollen between February and September at one greenhouse and as much as 73% during July at another. Therefore, greenhouse tomato growers are probably not obtaining maximum pollination benefit from bumblebee colonies and should address methods to reduce their foraging outside the greenhouse. Key words: Bumblebee, Bombus occidentalis, Bombus impatiens, pollen, greenhouse, tomato

RésuméUne justification d'institutions morales ou politiques doit fournir aux gens une motivation pour agir en conformité avec ses diktats. Cela étant admis, je soutiens que le contractualisme est la seule méthode plausible par laquelle une telle justification puisse être fournie. Les contractualistes soutiennent que les institutions morales ou politiques sont justifiées dans la mesure où elles seraient le résultat d'une entente conclue par des agents rationnels. Les agents rationnels agissent de façon à maximiser lew utilité attendue. Lorsque tous les facteurs sont pris en considération, une entente conclue par des agents rationnels doit done maximiser leur utilité attendue. À partir de cela, et de l'observation du lieu commun selon lequel des personnes différentes ont des préférences différentes, je soutiens que les justifications contractualistes sont relatives à la fois sur le plan normatif et sur leplan méta-éthique. Tant les règies ainsi justifiées que la procédure employée pour produire la justification doivent être identifiées relativement à des populations particulières.

This article explores the recent history and significance of unconventional natural gas development in the Marcellus region of Pennsylvania, including a look at the state’s historical background on hydrocarbon production, the effect of political and social media campaigns against development activities and the outlook for the future. In consultation with industry and environmental groups, Pennsylvania’s state government has crafted rules and regulations allowing responsible development to proceed, helping industry secure and retain its licence to operate in the process. This success was further made possible by an early and robust public engagement strategy that refuted misinformation and provided proper context for both the benefits and challenges inherent in resource development. However, in neighbouring states like New York and Maryland, similar public strategies and campaigns in support of development were not as quickly assembled and mobilised. The contrasting histories (and final results) help provide a template of lessons learned for other areas considering shale development, including an opportunity to avoid the kinds of mistakes that have led to moratoria, bans or other restrictions on specific well stimulation technologies, such as hydraulic fracturing.