The Systems Measurement of Mammalian Biotas, Part Two.

For a recent publication, the authors identified a seven-region model of mammal family distribution patterns, in which each unit contributes equally to the system's overall statistical characteristics of diversity, despite its individual units having measurably different levels of diversity and endemism. This systemization presents a highly efficient descriptive model that can possibly be interpreted as a form of natural classification. An additional analysis of the same mode is described here, in which the seven-region model of the distribution of mammal families' spatial affinities is shown to closely approach a most-probable-state arrangement, as assessed through combinatorics, raising some important questions about how macroevolutionary patterns might self-organize spatially. One of the possible practical applications of the overall approach is to areal representation; statistical moments of the underlying world patterns can be used to characterize faunal statuses at any individual location by relating the latter to the former. Through this approach, classical concepts such as corridors, tracks, and transition zones might be re-examined in a manner that better lends itself to hypothesis testing. An arbitrarily chosen bounded area, the conterminous United States, is treated in this fashion by way of illustration.

Evolution and Biogeography, and the Systems Measurement of Mammalian Biotas.

Biological evolution is generally regarded as a stochastic or probabilistic process, per the ideas of Darwin in the nineteenth century. Even if this is true at the meso-scale, it still may, however, be impacted by overarching constraints that we have not yet identified. In this paper, we revisit the subject of mammal faunal regions with a mind to explore a potential kind of macroevolutionary influence. We first identify an optimum seven-region mammal faunal classification system based on spatial and phylogenetic data from a comprehensive 2013 review, and then examine the possibility that this classification provides supporting evidence for a Spinoza-influenced philosophical/theoretical model of the "natural system" concept developed by one of the authors in the 1980s. The hierarchical pattern of regional affinities revealed does do this.

Bioequivalence of saxagliptin/dapagliflozin fixed-dose combination tablets compared with coadministration of the individual tablets to healthy subjects.

Saxagliptin and dapagliflozin are individually indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The bioequivalence of saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg fixed-dose combination (FDC) tablets compared with coadministration of the individual tablets and the food effect on both strengths of saxagliptin/dapagliflozin FDCs were evaluated in this open-label, randomized, single-dose crossover study. Healthy subjects were randomized to saxagliptin 2.5 mg + dapagliflozin 5 mg fasted, 2.5/5 mg FDC fasted, 2.5/5 mg FDC fed (Cohort 1) or saxagliptin 5 mg + dapagliflozin 10 mg fasted, 5/10 mg FDC fasted, 5/10 mg FDC fed (Cohort 2). Serial blood samples for pharmacokinetics of saxagliptin and dapagliflozin were obtained predose and up to 60 h postdose. Bioequivalence of FDC tablets versus individual components was concluded if the 90% CIs for FDC to individual component geometric mean ratios of C max, AUC 0-T, and AUC inf of both analytes were between 0.80 and 1.25. Seventy-two subjects were randomized; 71 (98.6%) completed the study. Saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg FDC tablets were bioequivalent to the individual tablets administered concomitantly. Food had no clinically meaningful effect on saxagliptin or dapagliflozin overall systemic exposure. Saxagliptin/dapagliflozin FDC tablets were bioequivalent to coadministration of the individual components in healthy subjects under fasted conditions and food had no clinically meaningful effect on bioavailability.

Alfred Russel Wallace and the road to natural selection, 1844-1858.

Conventional wisdom has had it that the naturalist Alfred Russel Wallace and his colleague Henry Walter Bates journeyed to the Amazon in 1848 with two intentions in mind: to collect natural history specimens, and to consider evidential materials that might reveal the causal basis of organic evolution. This understanding has been questioned recently by the historian John van Wyhe, who points out that with regard to the second matter, at least, there appears to be no evidence of a "smoking gun" variety proving it so. In the present essay the circumstances of Wallace's interest in the matter are reviewed, and van Wyhe is taken to task with alternate explanations for the facts he introduces in his argument. The conclusion is that Wallace almost certainly did have the second objective in mind when he left for both the Amazon, and the Far East.

Wallace, Darwin and Ternate 1858.

Recent debates on the mailing date of Alfred Russel Wallace's 'Ternate essay' to Charles Darwin in the spring of 1858 have ignored certain details that, once taken into account, alter the matter considerably. Here, a closer look is taken at the critical question of whether Wallace's manuscript-accompanying letter represented a reply to the Darwin letter that arrived in Ternate on 9 March; it is concluded that it very probably did not.

Alfred Russel Wallace's world of final causes.

Alfred Russel Wallace (1823-1913) is an important figure in the history of science, but there remain many questions about the nature of his world view, and how it developed. Here, Wallace's appreciation of the role of final causes in evolution is linked to some of its probable origins, with an emphasis on the influence of Alexander von Humboldt (1769-1859). The question is then asked whether a final causes-based scientific agenda might be possible, and answered by drawing attention to two current efforts in that direction by Adrian Bejan, and by the author. A sketch of the latter approach, adapted from Spinozian thinking, is given, with an empirical example involving drainage basin morphology that suggests structural influences of a final causes sort.

"In space" or "as space"?: a new model.

In this analysis natural systems are posed to subsystemize in a manner facilitating both structured information/energy sharing and an entropy maximization process projecting a three-dimensional, spatial, outcome. Numerical simulations were first carried out to determine whether n × n input-output matrices could, once entropy-maximized, project a three-dimensional Euclidean metric. Only 4 × 4 matrices could; a small proportion passed the test. Larger proportions passed when grouped random patterns on and within two- and three-dimensional forms were tested. Topographical patterns within 31 stream basin systems in the state of Kentucky, USA, were then similarly investigated, anticipating that the spatial configuration of elevations within each basin would provide evidence of evolutionary control when interpreted as internal group relations. Twenty-eight of thirty-one of the systems pass the test unambiguously, with the remaining three approaching or reaching passage when sampling density is increased. Two measures of subsystem-level redundancies are also introduced; these show: (1) surprisingly, minimized internal redundancy levels at the four subsystems level of analysis of the stream systems (as opposed to the five or six, in contrast with the simulations), and (2) much lower average levels than those obtained in the simulations at the same dimensions, both suggesting a preferred evolutionary path under real world conditions.

Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects.

BACKGROUND AND OBJECTIVES: As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer potential for increased patient compliance with the convenience of once-daily dosing. Two bioequivalence studies assessed the fed-state bioequivalence of saxagliptin/metformin XR 5 mg/500 mg FDC (study 1) and saxagliptin/metformin XR 5 mg/1000 mg FDC (study 2) relative to the same dosage strengths of individual component tablets administered concurrently. The effect of food on saxagliptin and metformin pharmacokinetics from the saxagliptin/metformin XR 5 mg/500 mg FDC and their steady-state pharmacokinetics from the saxagliptin/metformin XR 5 mg/1000 mg were also investigated. METHODS: These were randomized, open-label, single-dose, three-period, three-treatment, crossover studies in healthy subjects (n = 30 in each study). The treatments in study 1 were a saxagliptin/metformin XR 5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 5 mg and metformin XR 500 mg co-administered in the fed state. The treatments in study 2 were a saxagliptin/metformin XR 5 mg/1000 mg FDC tablet in the fed state, saxagliptin 5 mg and 2 × metformin XR 500 mg co-administered in the fed state, and saxagliptin/metformin XR 5 mg/1000 mg FDC once daily for 4 days in the fed state to assess steady-state pharmacokinetics. The safety and tolerability of each treatment were also evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components as the limits of the 90% confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within 0.800 to 1.250. Compared with the fasted state, food did not have a meaningful effect on the pharmacokinetics of saxagliptin and metformin when administered as the saxagliptin/metformin XR 5 mg/500 mg FDC. The saxagliptin/metformin XR 5 mg/1000 mg FDC showed consistent pharmacokinetics at steady state without evidence of dose dumping. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSION: Saxagliptin/metformin XR 5 mg/500 mg and saxagliptin/metformin XR 5 mg/1000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths. Additionally, food had little effect on the pharmacokinetics of saxagliptin and metformin administered in the saxagliptin/metformin XR 5 mg/500 mg FDC and the steady-state pharmacokinetics of the saxagliptin/metformin XR 5 mg/1000 mg FDC was consistent over time. No unexpected safety findings were observed with saxagliptin/metformin XR administration. The tolerability of the FDC of saxagliptin/metformin XR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin XR FDC tablets. TRIALS REGISTRATION: ClinicalTrials.gov Identifiers: NCT01192139 and NCT01192152.