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Opioid antagonists may mitigate medication-associated weight gain and/or metabolic dysregulation. ENLIGHTEN-2 evaluated a combination of olanzapine and the opioid antagonist samidorphan (OLZ/SAM) vs olanzapine for effects on weight gain and metabolic parameters over 24 weeks in adults with stable schizophrenia.
This phase 3, double-blind study (ClinicalTrials.gov: NCT02694328) enrolled adults 18–55 yo with stable schizophrenia, randomized 1:1 to once-daily OLZ/SAM or olanzapine. Co-primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. Waist circumference and fasting metabolic parameters were also measured. Completers could enter a 52-week open-label safety extension.
561 patients were randomized: 550 were dosed, 538 had ≥1 post-baseline weight assessment, and 352 (64%) completed; 10.9% discontinued due to AEs. At week 24, least squares mean (SE) percent weight change from baseline was 4.21 (0.68)% with OLZ/SAM and 6.59 (0.67)% with olanzapine (difference, −2.38 [0.76]%; P=0.003). Fewer patients treated with OLZ/SAM (17.8%) had ≥10% weight gain vs olanzapine (29.8%; odds ratio=0.50; P=0.003). The change from baseline in waist circumference was significantly smaller with OLZ/SAM (P<0.001). Common AEs (≥10%) with OLZ/SAM and olanzapine were weight increased (24.8%, 36.2%), somnolence (21.2%, 18.1%), dry mouth (12.8%, 8.0%), and increased appetite (10.9%, 12.3%), respectively. Metabolic parameter changes were generally small and remained stable with long-term OLZ/SAM treatment.
OLZ/SAM treatment limited weight gain associated with olanzapine. Metabolic parameter changes were generally small, similar between groups over 24 weeks, and remained stable over an additional 52 weeks of open-label OLZ/SAM treatment.
The Executive Committee Working Group on “Cosmic Light” was created in 2014 (at its EC94 Meeting, Apr.30-May 2, Canberra, Australia), in preparation of the contribution of the IAU to the UNESCO “2015 International Year of Light and Light Technologies” (IYL2015), which had been approved by the UN in December 2013 (see http://www.light2015.org/Home.html).
Fossils of Columbian mammoths (Mammuthus columbi) and pygmy mammoths (Mammuthus exilis) have been reported from Channel Islands National Park, California. Most date to the last glacial period (Marine Isotope Stage [MIS] 2), but a tusk of M. exilis (or immature M. columbi) was found in the lowest marine terrace of Santa Rosa Island. Uranium-series dating of corals yielded ages from 83.8 ± 0.6 ka to 78.6 ± 0.5 ka, correlating the terrace with MIS 5.1, a time of relatively high sea level. Mammoths likely immigrated to the islands by swimming during the glacial periods MIS 6 (~ 150 ka) or MIS 8 (~ 250 ka), when sea level was low and the island–mainland distance was minimal, as during MIS 2. Earliest mammoth immigration to the islands likely occurred late enough in the Quaternary that uplift of the islands and the mainland decreased the swimming distance to a range that could be accomplished by mammoths. Results challenge the hypothesis that climate change, vegetation change, and decreased land area from sea-level rise were the causes of mammoth extinction at the Pleistocene/Holocene boundary on the Channel Islands. Pre-MIS 2 mammoth populations would have experienced similar or even more dramatic changes at the MIS 6/5.5 transition.
Curaçao has reef terraces with the potential to provide sea-level histories of interglacial periods. Ages of the Hato (upper) unit of the “Lower Terrace” indicate that this reef dates to the last interglacial period, Marine Isotope Stage (MIS) 5.5. On Curaçao, this high sea stand lasted at least 8000 yr (~ 126 to ~ 118 ka). Elevations and age of this reef show that late Quaternary uplift rates on Curaçao are low, 0.026–0.054 m/ka, consistent with its tectonic setting. Ages of ~ 200 ka for corals from the older Cortalein unit of the Lower Terrace correlate this reef to MIS 7, with paleo-sea level estimates ranging from − 3.3 m to + 2.3 m. The estimates are in agreement with those for MIS 7 made from other localities and indicate that the penultimate interglacial period was a time of significant warmth, on a par with the present interglacial period. The ~ 400 ka (MIS 11) Middle Terrace I on Curaçao, dated by others, may have formed from a paleo-sea level of + 8.3 to + 10.0 m, or (less likely) + 17 m to + 20 m. The lower estimates are conservative compared to previous studies, but still require major ice sheet loss from Greenland and Antarctica.
The ability to repress P-element-induced gonadal dysgenesis was studied in 14 wild-type strains of D. melanogaster derived from populations in the central and eastern United States. Females from each of these strains had a high ability to repress gonadal dysgenesis in their daughters. Reciprocal hybrids produced by crossing each of the wild-type strains with an M strain demonstrated that repression ability was determined by a complex mixture of chromosomal and cytoplasmic factors. Cytoplasmic transmission of repression ability was observed in all 14 strains and chromosomal transmission was observed in 12 of them. Genomic Southern blots indicated that four of the strains possessed a particular type of P element, called KP, which has been proposed to account for the chromosomal transmission of repression ability. However, in this study several of the strains that lacked KP elements exhibited as much chromosomal transmission of repression ability as the strains that had KP elements, suggesting that other kinds of P elements may be involved.
Great changes in the character and interrelations of western political societies were in progress during the sixteenth and seventeenth centuries. Early modern philosophers either directly witnessed these changes or were able to reflect upon them from no great distance, as crucial elements of their recent political history. Unsurprisingly, then, early modern political philosophy was in important respects preoccupied with the theoretical underpinnings of the emerging political order, with its new institutions and new expectations of citizens and public officials. The theories advanced by political philosophers of the period in turn played their own modest roles in influencing the development of the modern political institutions with which we are familiar today. Their questions and problems were thus importantly related to our own, which allows early modern political philosophy to speak to many of us in a way that is perhaps not fully possible for the political philosophies of earlier periods.
I will stress here two great “divides” or transitions within the period that can help us to understand some of the most salient features of early modern political philosophy. The first of these divides is the theoretical divide between what we can call “political naturalism” and “political antinaturalism.” The second is the historical transition (mirrored by a corresponding transition in political theories) from political societies that existed as complex, hierarchical structures of overlapping religious and contractual relationships (such as those that characterized empire and the feudal order) to political societies that began to take the form of modern, sovereign, territorial states.
Even if the considerations offered in the preceding chapter conclusively defeat political anarchism, they are not by themselves sufficient to refute philosophical anarchism because they do not explain why one has a duty to obey the law. A citizen's political responsibilities have yet to be established because the focus to this point has been exclusively upon the permissibility of a state's coercing its constituents, not the political duties of those coerced. I am hopeful that we can develop an adequate account of our duty to obey the law, however, by building upon the defense of statism offered earlier. In particular, I think that just as samaritanism is crucial to justifying the state's coercion, it is the key to explaining our political duties.
Samaritan Duties and Fairness
The first thing to notice is that the peril of others can explain not only why one may permissibly be coerced, it can also explain why one is obligated to assist those who are imperiled. (Indeed, if anything, it is more common and less controversial to posit samaritan duties than to defend the existence of a samaritan right to coerce.) Thus, just as I invoked samaritanism to explain why Beth may permissibly commandeer Cathy's car if it is the only way to get Amy to the hospital in time to save her life, samaritanism can help explain why Beth has a duty to take Amy to the hospital and/or why Cathy has a duty to loan her car to the cause.
Given my specification that we have a moral duty to obey only the just laws of a legitimate regime, it is natural to explore what types of laws are in fact just. This matter is especially pressing for those who draw on samaritanism because a critic might worry that samaritan considerations are too restricted to justify most of the functions that modern bureaucratic states legitimately perform. In particular, samaritanism appears incapable of justifying all those functions that either require extremely costly sacrifices or do not rescue anyone from peril. To show how an advocate of samaritanism might respond to this challenge, this chapter focuses on two types of laws: those that require citizens to vote and those that draft citizens into compulsory military service. In the end, I conclude that an approach based on samaritanism has more resources to explain governmental functions than might initially be apparent, but that we should nonetheless be open to the possibility that many of the practices of existing states, even liberal democratic ones, are entirely unjustified.
Even if samaritan considerations cannot justify many of the functions that modern bureaucratic states regularly assign themselves, there are two reasons not to dismiss the approach on these grounds. First, as I mentioned in the previous chapter, there is no reason why defenders of the samaritan approach cannot appeal to other considerations that justify various additional obligations.
In the discussion that follows, I will defend a division of the available theories of the duty to obey the law into three groups or “families.” This division will allow me (in this section) to discuss the merits and difficulties of two of these families briefly and in very general terms, largely summarizing arguments that I have made before. In particular, I will distinguish (what I call) Associative, Transactional, and Natural Duty theories of a duty to obey. Associative accounts ground our duty to obey in our nonvoluntary occupation of certain duty-laden social roles, while Transactional accounts ground our duty (or obligation) to obey in our morally significant interactions with our states or fellow citizens. I will attempt (in this chapter) to explain and deal with these first two families of theories by revealing what I take to be the fatal defects that infect all possible members of the families, saving my more detailed discussion and criticism for the last family. Chapter 7 will then be devoted to a much more careful examination of the third – and currently the most popular – of these families of theories. Natural Duty theories of the duty to obey the law are those that ground our duty to obey not in who we are (as in Associative accounts) or in what we've done or enjoyed (as in Transactional accounts), but rather either (a) in the moral importance of advancing some impartial moral good or (b) in some moral duty thought to be owed by all persons to all others as moral equals, regardless of roles, relationships, or transactions.
I have discussed the principal variants of Natural Duty theories of the duty to obey the law that are being defended by contemporary political and legal philosophers/theorists. But the influence of this family of theories in fact appears to extend well beyond the self-proclaimed family members. Many theories of the duty to obey that are presented by their defenders in Associative or Transactional language seem in actuality to rest more heavily on Natural Duty foundations. Let me note here just two prominent recent examples of this tendency. The best-known recent defense of an (allegedly) Associative account of the duty to obey – namely, Dworkin's – appears to justify its support for the moral force of Associative ties precisely by appealing (non-Associatively) to a “natural duty” that we have “to honor our responsibilities under social practices that define groups and attach special responsibilities to membership.” Similarly, George Klosko's prominent recent defense of a fairness theory of obligatory obedience (which purports to be a Transactional reciprocation theory [to use my classifications]) seems actually to be far less concerned with fairness, properly understood, than with the needs of those who depend on the public goods states provide. It is the value or importance of these public goods (their “presumptive” status) – and some unacknowledged natural duty to help make them generally available in our society – that seems to ground required obedience in Klosko's theory, not (as should be the case if fairness is really the issue) our acceptance of benefits, our free participation in a genuinely cooperative scheme, or the ways in which refusal to obey would take advantage of others.