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The Caribbean was one of the last regions of the Americas to be settled by humans, but where they came from and how and when they reached the islands remain unclear. We generated genome-wide data for 93 ancient Caribbean islanders dating between 3200 and 400 calibrated years before the present and found evidence of at least three separate dispersals into the region, including two early dispersals into the Western Caribbean, one of which seems connected to radiation events in North America. This was followed by a later expansion from South America. We also detected genetic differences between the early settlers and the newcomers from South America, with almost no evidence of admixture. Our results add to our understanding of the initial peopling of the Caribbean and the movements of Archaic Age peoples in the Americas., The research was funded by the Max Planck Society and the European Research Council under the 7th Framework Program (grant agreement no. 319209, ERC Synergy Project NEXUS1492). H.S. was supported by the HERA (Humanities in the European Research Area) Joint Research Program “Uses of the Past” (CitiGen) and the European Union’s Horizon 2020 research and innovation program under grant agreement no. 649307. W.J.P. and M.A.N.-C. were supported by the National Science Foundation (BCS-0612727 and BCS1622479). C.L.-F. was supported by a grant from the Ministry of Science, Innovation and Universities (PGC2018-0955931-B-100, AEI/FEDER, UE). M.R. was supported by the Social Sciences and Humanities Research Council of Canada (435-2016-0529). M.R., Y.C.d.A., U.M.G.H., and S.T.H.G. were supported by the Social Sciences and Humanities Research Council of Canada (standard research grant SSHRC ‐ 410‐2011‐1179 and SSHRC postdoctoral fellowship ‐ 756‐2016‐0180) and several University of Winnipeg internal grants (Major grant 2017, 2018; Partnership Development grant 2017, 2018; and Discretionary grant 2017, 2018).

Previous studies suggest that the roots of school dropout (a) can be established early in life, (b) are likely to involve multilevel factors (home, child, classroom) operating prior to and during the elementary school years, and (c) can be identified by 3rd grade. The decision to drop out of school is thus a dynamic developmental process that can begin with disengagement in elementary school. Yet few studies have examined the multilevel factors that might contribute to children's early disengagement from school. In the present study, we examined associations between household chaos (i.e., disorganization and instability) from birth to age 5 and student (dis)engagement in third grade. We also examined positive parenting in early childhood (6-60 months) and child self-regulatory skills at kindergarten as potential mediators in this pathway. Participants were 1,097 children who participated in the Family Life Project, a longitudinal study of the development of children living in underresourced high poverty rural areas. Study questions were addressed using structural equation models. Results indicated that, even after taking into account a considerable number of covariates, early positive parenting and children's self-regulatory skills were viable process mechanisms through which early household disorganization, but not instability, was linked to student (dis)engagement in third grade. Findings are discussed with respect to the multilevel proximal forces at play in children's risk for early disengagement from school. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In the Traveling Salesman Problem (TSP), a salesman wants to visit a set of cities and return home. There is a cost \(c_{ij}\) of traveling from city i to city j, which is the same in either direction for the Symmetric TSP. The objective is to visit each city exactly once, minimizing total travel costs. In the Graphical TSP, a city may be visited more than once, which may be necessary on a sparse graph. We present a new integer programming formulation for the Graphical TSP requiring only two classes of constraints that are either polynomial in number or polynomially separable, while addressing an open question proposed by Denis Naddef.

This study considered the quality and stability of infant and toddler nonparental child care from 6 to 36 months in relation to language, social, and academic skills measured proximally at 36 months and distally at kindergarten. Quality was measured separately as caregiver-child verbal interactions and caregiver sensitivity, and stability was measured as having fewer sequential child-care caregivers. This longitudinal examination involved a subsample (N = 1,055) from the Family Life Project, a representative sample of families living in rural counties in the United States. Structural equation modeling revealed that children who experienced more positive caregiver-child verbal interactions had higher 36-month language skills, which indirectly led to higher kindergarten academic and social skills. Children who experienced more caregiver stability had higher kindergarten social skills.

The interfacial interactions between methylene diphenyl di-isocyanate (MDI) and polymeric MDI (PMDI) with 316L stainless steel have been studied in order to understand the adhesion properties of polyurethane based adhesives (containing free isocyanate groups) on metal surfaces. A thin (< 5 nm) layer of MDI and PMDI was deposited on the surface of clean 316L stainless steel and then analysed by X-ray photoelectron spectroscopy (XPS) and time of flight secondary ion mass spectrometry (ToF-SIMS). By using density functional theory (DFT) methods for the interpretation of XPS data, the presence of specific interactions between the adsorbate and the substrate was established. The reaction between isocyanate and metal hydroxyl groups with the formation of urethane-like bonding with the metal was observed. The formation of hydrogen bonds between the isocyanate nitrogen and the hydroxyl groups and the formation of nitrogen-metal double bond, as consequence of the cycloaddition reaction between isocyanate and metal oxide, are also proposed.

Prior research indicates that preschool classroom quality is positively associated with children’s emergent academic skills at the end of the preschool period, but these associations appear to diminish during kindergarten (K). To consider the accumulation of classroom experiences during preschool and K, data were drawn from a sample of children (N = 1015) who participated in state-funded pre-K programs across six states and were followed into the spring of K. We examined if pre-K and K classroom quality were associated with children’s language, literacy, and mathematics skills in the spring of K after controlling for pre-K entry skills, child background demographics, and other classroom covariates. Classroom quality was assessed with the Classroom Assessment Scoring System. We found that additive cumulative effects described associations between classroom quality and children’s language and literacy outcomes. For language skills, higher-quality pre-K Instructional Support predicted better K language skills at all levels of Instructional Support quality in K, but higher-quality K Instructional Support also contributed to the prediction of better K language skills in an additive manner. For literacy skills, higher-quality pre-K Instructional Support, Emotional Support, and Classroom Management predicted better K literacy skills at all levels of K quality, but each domain of K quality also contributed to the prediction of better K literacy skills in an additive manner. In contrast, for mathematics, we found that multiplicative cumulative effects described associations between classroom quality and K mathematics skills such that the positive predictive effect of pre-K Instructional Support and Emotional Support was enhanced as the level of K quality increased in each of these domains, respectively. Moreover, sensitivity analyses revealed that higher-quality pre-K Instructional Support and Emotional Support significantly predicted better K mathematics skills for children who experienced high, but not average or low levels of K quality in these domains, respectively. Implications are discussed in relation to classroom quality alignment during pre-K and the early elementary grades.

Early literacy skills play an important role in children’s success in school. Especially important to better literacy skills may be the quality of the classroom environment (emotional support, classroom organization, and instructional support) across the early years of schooling. This study used an a priori threshold of quality approach to understanding the possible link between the number of years of better classroom quality over four years, from kindergarten through third grade, in relation to children’s literacy skills by third grade. This study examined a representative sample of 1292 children followed from birth who lived in low-wealth rural counties in the United States. These children were followed into school with classroom observations conducted each year from kindergarten through third grade and literacy related achievement measures in pre-kindergarten and third grade. Findings suggested that even after controlling for poverty related variables, the quality of the home environment, school entry literacy skills, and teacher rated literacy instruction, children who had more years of better classroom quality had higher third grade literacy scores. Additionally, we found an interaction effect, suggesting that children who entered kindergarten with lower emergent literacy skills benefited more from a greater number of years of better classroom quality in relation to reading comprehension in third grade. Thus, more years of better classroom quality may help in narrowing the gap between those who enter kindergarten with higher literacy skills and those who enter with lower literacy skills.

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed Cmax and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds.

The gap in school readiness skills between children growing up in poverty and other children has become a major policy issue as increasing proportions of families are living in poverty, especially in low-wealth rural communities. The purpose of this paper was to document the degree to which depth, persistence, and timing of poverty was related to the early development of children in a representative sample of 1,292 families in two of the four poor rural regions in the United States, labeled Appalachia and the Black South. Analyses documented the emergence of the poverty gap in the child’s first 5 years of life, asking when the gap emerged and whether it continued to grow through the early childhood period. Findings indicated that families who experienced poverty during the child’s first 2-years showed substantially lower cognitive, language, executive functioning, and social skills by 2 to 3 years of age (0.5 to 1.0 SD difference) and these gaps appeared to stabilize between 3 and 5 years of age. Transitions into deep poverty during the preschool period (3- to 5-years) were also related to substantially lower scores, and to a lesser extent, transitions out of poverty were related to higher skill levels. Accounting for baseline demographic and maternal characteristics diminished the poverty gap, but did not eliminate it. The poverty gaps at 3-years in language, executive functioning, and social skills accounted for much of the poverty gaps observed at 5-years. Policy implications for early care and education programming are discussed.

We explore three issues related to the practice of preventive medicine. First, how does the dearth of preventive medicine physicians on state licensure boards affect quality of medical care? Second, should a process be established to assess the training and skills of candidates for population health positions, like the "credentialing" or "privilege-granting" process used by hospitals and health systems for clinical positions? And third, how should the pervasive lack of recognition of preventive medicine as a bona fide medical specialty be addressed? In exploring these issues, we conclude that preventive medicine physicians are critical to the US health care ecosystem at every level, and to building a dominant culture of prevention. Preventive medicine physicians are actively engaged in the practice of medicine and should be party to the same licensure, credentialing, and privilege-granting procedures as all other specialties. Further, we raise a call to action to our profession to define and raise awareness of preventive medicine, participate in state licensure boards, and establish clear standards of practice for which we are uniquely trained and capable.

Download : Download high-res image (149KB) Download : Download full-size image Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2′-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2′-deoxy-2′-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

The positive effects of pre-kindergarten (pre-K) programming may be enhanced in later grades for children who subsequently experience high-quality educational environments in elementary school. The current study tested this hypothesis in relation to the effects of North Carolina's NC Pre-K program on child outcomes at the end of kindergarten, including language, literacy, mathematics, and working memory. Measures of elementary school quality were examined as moderators of the NC Pre-K effects, including school-wide academic proficiency and school-wide growth in academic achievement. We found no reliable effects of NC Pre-K participation for children attending elementary schools with average levels of quality. However, the positive effects of NC Pre-K participation on language and working memory skills were evident for children attending elementary schools with higher levels of academic proficiency and academic growth, respectively. No evidence of moderation was found in relation to literacy and mathematics skills.

This article explores the political economy of Closed-Circuit Television (CCTV) in Australia, providing new insights into the relationship between government policy and its economic implications. I have rationalised state-sponsored street cameras as a component in the cultivation of consent between the state and local communities; a mechanism for government to facilitate the flow of public funds to business through arrangements that are virtually unchecked and non-evidence based; a mechanism for government to facilitate profitable opportunities in and beyond the security technologies industry; and, a mechanism to normalise hegemonic social and political relations at the level of discourse. This article explores how government has assisted growth in the security industry in Australia. I draw on a case study about Kiama Municipal Council’s decision in 2014 to accept funding from the Abbott Government to install CCTV cameras through the Safer Streets Programme. This is despite historically low crime rates in Kiama and an inability to demonstrate broad support for the programme in the local community. This study reveals how politicians have cultivated support for CCTV at the local level and pressured councils to install these systems despite a lack of evidence they reduce, deter or prevent crime. Examined is how the footage captured on local council CCTV has been distributed and its meanings mediated by political and commercial groups. I argue that the politics of CCTV dissemination in Australia is entwined with the imperatives of electoral success and commercial opportunity—a coalescent relationship evident in the Safer Streets Programme. Furthermore, the efficacy of CCTV as an electoral tool in Australia is explained via the proposition that street cameras perform a central role in the discourses and political economy of the state.

A major developmental task for young children in the United States involves the acquisition of knowledge about the letters in the English alphabet. In the current study, we examined the growth trajectories of children's letter name knowledge (LNK) during pre-kindergarten and kindergarten. A diverse sample of 1015 children was drawn from the National Center for Early Development and Learning Multi-State Study of Pre-Kindergarten. Latent class growth analyses were used to identify three heterogeneous classes of children based on their LNK growth trajectories. Children's fall-of-pre-kindergarten language skills were associated with trajectory class membership, which in turn was associated with children's spring-of-kindergarten literacy skills. We also found that the association between children's fall-of-pre-kindergarten language skills and spring-of-kindergarten literacy skills was partially mediated by trajectory class membership. These findings point to the importance of LNK skill development as a marker variable to monitor and support children's emergent literacy development.

Our HCV research program investigated novel 2′-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5′-phosphoramidate prodrug of 2′-deoxy-2′-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5′-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).

Silicon wafers, covered with different thickness layers of polystyrene, were analysed by XPS. High resolution spectra of the C1s shake-up satellite, due to the π-π* transition of the aromatic ring, were compared. A shift in the shake-up binding energy represents a change in the electronic transition energy and so in the energy of the molecular orbital. This made it possible to assess and confirm an interaction between the π electrons of the phenyl ring and the silanol groups present on the surface of the silicon. Copyright © 2015 John Wiley & Sons, Ltd.

The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility–permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility–permeability interplay. All formulations significantly increased etoposide’s apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility–permeability tradeoff associated with other formulation techniques. Accounting for the solubility–permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs.

This is a pictorial essay in which we review and illustrate a variety of thoracic injuries related to blunt trauma. Non-aortic blunt thoracic trauma can be divided anatomically into injuries of the chest wall, lungs, pleura, mediastinum, and diaphragm. Some injuries involve more than one anatomic compartment, and multiple injuries commonly coexist. This article provides common imaging findings and discussion of both common and uncommon but critical thoracic injuries encountered.

Acid and redox reaction rates of CH3OH-O2 mixtures on polyoxometalate (POM) clusters, together with isotopic, spectroscopic, and theoretical assessments of catalyst properties and reaction pathways, were used to define rigorous descriptors of reactivity and to probe the compositional effects for oxidative dehydrogenation (ODH) and dehydration reactions. 31P-MAS NMR, transmission electron microscopy and titrations of protons with di-tert-butylpyridine during catalysis showed that POM clusters retained their Keggin structure upon dispersion on SiO2 and after use in CH3OH reactions. The effects of CH3OH and O2 pressures and of D-substitution on ODH rates show that C–H activation in molecularly adsorbed CH3OH is the sole kinetically relevant step and leads to reduced centers as intermediates present at low coverages; their concentrations, measured from UV–vis spectra obtained during catalysis, are consistent with the effects of CH3OH/O2 ratios predicted from the elementary steps proposed. First-order ODH rate...

Acid strength effects on alkane isomerization turnover rates and selectivities are probed using hexene isomers as reactants on bifunctional catalysts containing tungsten Keggin polyoxometalates (POM) with different central atoms and exhibiting well-defined structures amenable to reliable estimates of deprotonation energies (DPE) as rigorous descriptors of acid strength. Titrations of protons with hindered bases during catalysis and mechanistic interpretations of rate data on POM acids in terms of a common sequence of elementary steps give isomerization rate constants that decrease exponentially with increasing DPE. The sensitivity to acid strength is the same for all interconversions among isomeric hexenes because their respective transition states are similar in the amount and localized character of their cationic charges, which determine, in turn, the extent to which the ionic and covalent interactions that determine DPE are recovered upon formation of ion pairs at transition states. The ratios of rate constants for such interconversions, and thus selectivities, are independent of acid strength and their magnitude merely reflects the stability of the gaseous analogs of their respective transition states on all acids.

The effects of heteroatom identity (Al 3+ ,G a 3+ ,F e 3+ ,o r B 3+ ), concentration and location on catalysis by MFI zeolites are examined and interpreted mechanistically using methanol dehydration rate constants and density functional theory estimates of acid strength (deprotonation energies, DPE). In doing so, we shed light on the concomitant effects of confinement and acid strength on catalytic reactivity. Rate constants (per H + from pyridine titrations during catalysis) in the first-order and zero-order kinetic regimes decreased exponentially as the DPE of MFI with different heteroatoms increased. These trends reflect a decrease in the stability of ion-pair transition states relative to the relevant precursors (H-bonded methanol and methanol dimers, respectively, for these two regimes) with decreasing acid strength and resemble those in mesoporous solid acids (e.g., polyoxometalates). Confinement effects, weaker in mesoporous solids, give larger rate constants on MFI than on POM clusters with similar DPE. Such reactivity enhancements reflect the effects of MFI voids that solvate transition states preferentially over smaller precursors via van der Waals interactions with the confining voids. Both dehydration rate constants on MFI with 0.7– 2.4 H + per unit cell volume (5.2 nm 3 ) are independent of Al or H + densities, indicating that neither H

A reaction scheme is proposed to account for the liberation of 4-benzylaniline from 4-benzylaniline hydrochloride, using chlorobenzene as a solvent at a temperature of 373 K. Two operational regimes are explored: “closed” reaction conditions correspond to the retention of evolved hydrogen chloride gas within the reaction medium, whereas an “open” system permits gaseous hydrogen chloride to be released from the reaction medium. The solution phase chemistry is analyzed by 1H NMR spectroscopy. Complete liberation of solvated 4-benzylaniline from solid 4-benzylaniline hydrochloride is possible under “open” conditions, with the entropically favored conversion of solvated hydrogen chloride to the gaseous phase thought to be the thermodynamic driver that effectively controls a series of interconnecting equilibria. A kinetic model is proposed to account for the observations of the open system.

Members of the Tequesta, a pre/proto-historic indigenous group of South Florida, cut thousands of postholes into the shallow limestone bedrock of the Metropolitan Square site, located in present-day Miami. Calcrete (limestone soil crust) formations found in and around these postholes serve as a geochemical repository attesting to various human and natural processes at the site. We present here the results of petrographic, total organic carbon (TOC), X-ray diffraction (XRD), X-ray fluorescence (XRF), and stable-isotope analysis, which were used in an attempt to relatively date posthole excavation and to identify patterns of changing site use. Ultimately, the combination of these methods yielded useful insights into paleoenvironment and proposed changes in site use, while failing to provide desired information on chronology. A combined geochemical approach such as that employed here would seem to hold potential for future study of sites located in calcareous/karstic contexts.

Veliparib (ABT-888) is largely eliminated as parent drug in human urine (70% of the dose). Renal unbound clearance exceeds glomerular filtration rate, suggesting the involvement of transporter-mediated active secretion. Clinically relevant pharmacokinetic interactions in the kidney have been associated with OAT1, OAT3, OCT2, MATE1, and MATE2K. In the present study, interactions of veliparib with these transporters were investigated. Veliparib inhibited OAT1, OAT3, OCT2, MATE1, and MATE2K with IC 50 values of 1371, 505, 3913, 69.9, and 69.5 μM, respectively. The clinical unbound maximum plasma concentration of veliparib after single oral dose of 50 mg (0.45 μM) is manyfold lower than IC 50 values for OAT1, OAT3, OCT2, MATE1, or MATE2K. These results indicate a low potential for drug–drug interaction (DDI) with OAT1/3, OCT2, or MATE1/2 K. Additional studies demonstrated that veliparib is a substrate of OCT2. In Oct1/Oct2 double-knockout mice, the plasma exposure of veliparib was increased by 1.5-fold, and the renal clearance was decreased by 1.8-fold as compared with wild-type mice, demonstrating that organic cation transporters contribute to the renal elimination in vivo. In summary, the in vitro transporter data for veliparib predicts minimal potential for an OAT1/3-, OCT2-, and MATE1/2 K-mediated DDI given the clinical exposure after single oral dose of 50 mg.

Bioarchaeological analysis of the MDM site (8DA11) in Miami, Florida (ad 400–1200) has identified human skeletal remains with lesions suggestive of and consistent with treponematosis. A population and epidemiological approach was utilised to compare the MDM site to geographically neighbouring skeletal samples from the Highland Beach mound (8PB11) (ad 600–1200) and Fort Center (8GL12) (ad 1–500/1000). These samples were then integrated with data from previous research on proliferative skeletal lesion prevalence on the Gulf Coast of Florida. Population comparisons suggest a higher prevalence of proliferative skeletal lesions in Atlantic coastal populations as opposed to the nearest sampled site from the interior (p

Background: More than 80–95% of adverse drug events occurring among renally impaired patients are related to excessive dosing. Objective: To assess current prescribing practices with antiinfectives for patients with estimated creatinine clearance (CrCl) less than 51 mL/min who were in a local health care system. Methods: Outpatient antiinfective prescriptions written during a 10-day period in July 2012 were reviewed. The following information was collected for each patient: age, sex, serum creatinine, weight, height, drug dose and schedule, and discharge unit/outpatient service. Kidney function was estimated by calculating CrCl using either the Cockcroft-Gault or the Jelliffe equation. Two resources were used to identify appropriate dosing for renal function; if the 2 resources differed, the stricter of the 2 was used for assessment. Institutional review board approval was obtained for this study. Results: A total of 91 prescriptions, written for 87 different patients, met inclusion criteria and were reviewed. Average CrCl and age among the study population was 37.82 mL/min, and 75.7 years, respectively. Doses were excessive in 30% of outpatient prescriptions. The most common medications involved in excessive dosing were trimethoprim/sulfamethoxazole (TMP/SMX), cephalexin, fluconazole, and acyclovir. TMP/SMX was dosed excessively in 80% of prescriptions. Both fluconazole and acyclovir were dosed excessively in 75% of prescriptions, while cephalexin was dosed in excess in 36% of prescriptions. A comparison of discharge units/outpatient services revealed that 56% of prescriptions from urgent care centers were dosed in excess, compared with 30% from hospital discharge, 20% from emergency department discharge, and 25% from outpatient services. Conclusions: Our study indicates that there is room for improvement when dosing antiinfective medications for outpatients with renal insufficiency. Appropriate renal dosing can help protect patients from dangerous toxicities and other adverse drug events.

The quality of methylene diphenyl diisocyanate (MDI) products, which are valuable feedstocks in the industrial manufacture of polyurethanes, can be compromised by the presence of color, presumed to arise from trace impurities. One undesired branch in the synthesis chain originates with phosgenation of diaryl ureas, formed from reactions between aryl isocyanates and polyamine precursors. Subsequent key steps include, (i) breakdown of the primary compounds, substituted chloroformamidine-N-carbonyl chlorides (CCC), to give aryl isocyanide dichlorides, ArNCCl2, (ii) an apparent equilibrium connecting CCC with aryl carbodiimides, and (iii) the thermolysis of ArNCCl2 in the presence of MDI. Color formation is associated directly with the last process; it involves several events, including HCl elimination from reaction of ArNCCl2 and MDI, formation of carbon-centered radicals, and a contribution from oxidation at the methylene bridge.

The synarcual is a structure incorporating the anterior vertebrae of the axial skeleton and occurs in vertebrate taxa such as the fossil group Placodermi and the Chondrichthyes (Holocephali, Batoidea). Although the synarcual varies morphologically in these groups, it represents the first indication, phylogenetically, of a differentiation of the vertebral column into separate regions. Among the placoderms, the synarcual of Cowralepis mclachlani Ritchie, 2005 (Arthrodira) shows substantial changes during ontogeny to produce an elongate, spool-shaped structure with a well-developed dorsal keel. Because the placoderm synarcual is covered in perichondral bone, the ontogenetic history of this Cowralepis specimen is preserved as it developed anteroposteriorly, dorsally and ventrally. As well, in the placoderm Materpiscis attenboroughi Long et al., 2008 (Ptyctodontida), incomplete fusion at the posterior synarcual margin indicates that both neural and haemal arch vertebral elements are added to the synarcual. A survey of placoderm synarcuals shows that taxa such as Materpiscis and Cowralepis are particularly informative because perichondral ossification occurs prior to synarcual fusion such that individual vertebral elements can be identified. In other placoderm synarcuals (e.g. Nefudina qalibahensis Lelievre et al., 1995; Rhenanida), cartilaginous vertebral elements fuse prior to perichondral ossification so that individual elements are more difficult to recognize. This ontogenetic development in placoderms can be compared to synarcual development in Recent chondrichthyans; the incorporation of neural and haemal elements is more similar to the holocephalans, but differs from the batoid chondrichthyans.

Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 μg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a markedly increased opportunity to maximize overall oral drug absorption.

Kinetic, spectroscopic, and chemical titration data indicate that differences in monomolecular isobutane cracking and dehydrogenation and methanol dehydration turnover rates (per H+) among FAU zeolites treated thermally with steam (H-USY) and then chemically with ammonium hexafluorosilicate (CD-HUSY) predominantly reflect differences in the size and solvating properties of their supercage voids rather than differences in acid strength. The number of protons on a given sample was measured consistently by titrations with Na+, with CH3 groups via reactions of dimethyl ether, and with 2,6-di-tert-butylpyridine during methanol dehydration catalysis; these titration values were also supported by commensurate changes in acidic OH infrared band areas upon exposure to titrant molecules. The number of protons, taken as the average of the three titration methods, was significantly smaller than the number of framework Al atoms (Alf) obtained from X-ray diffraction and 27Al magic angle spinning nuclear magnetic resonance spectroscopy on H-USY (0.35 H+/Alf) and CD-HUSY (0.69 H+/Alf). These data demonstrate that the ubiquitous use of Alf sites as structural proxies for active H+ sites in zeolites can be imprecise, apparently because distorted Al structures that are not associated with acidic protons are sometimes detected as Alf sites. Monomolecular isobutane cracking and dehydrogenation rate constants, normalized non-rigorously by the number of Alf species, decreased with increasing Na+ content on both H-USY and CD-HUSY samples and became undetectable at sub-stoichiometric exchange levels (0.32 and 0.72 Na+/Alf ratios, respectively), an unexpected finding attributed incorrectly in previous studies to the presence of minority “super-acidic” sites. These rate constants, when normalized rigorously by the number of residual H+ sites were independent of Na+ content on both H-USY and CD-HUSY samples, reflecting the stoichiometric replacement of protons that are uniform in reactivity by Na+ cations. Monomolecular isobutane cracking and dehydrogenation rate constants (per H+; 763 K), however, were higher on H-USY than CD-HUSY (by a factor of 1.4). Equilibrium constants for the formation of protonated methanol dimers via adsorption of gaseous methanol onto adsorbed methanol monomers, determined from kinetic studies of methanol dehydration to dimethyl ether (433 K), were also higher on H-USY than CD-HUSY (by a factor of 2.1). These larger constants predominantly reflect stronger dispersive interactions in H-USY, consistent with its smaller supercage voids that result from the occlusion of void space by extraframework Al (Alex) residues. These findings appear to clarify enduring controversies about the mechanistic interpretation of the effects of Na+ and Alex species on the catalytic reactivity of FAU zeolites. They also illustrate the need to normalize rates by the number of active sites instead of more convenient but less accurate structural proxies for such sites.

Phenyl and 4-methylphenyl isocyanide dichlorides are models for byproduct that may be formed in the later stages of certain polyurethane production chains. Photochemical electron paramagnetic resonance (EPR) studies (λ > 310 nm), using the spin trap, N-tert-butyl-α-phenylnitrone, confirm a previously made suggestion that ArN═CCl2 can behave as a chlorine radical source. EPR spectra recorded during and after irradiation and supported by simulations evolve over time and indicate formation of the short-lived spin trap–Cl• adduct and a longer lived benzoyl-N-tert-butylnitroxide radical. Photolysis of C6H5N═CCl2, either alone or mixed with methylene diaryl isocyanate species, in o-C6H4Cl2, a polyurethane process solvent, led to the formation of mixtures containing dichloro- and trichlorobiphenyl isomers.

Dimethyl ether (DME) homologation forms isobutane and triptane (2,2,3-trimethylbutane) with supra-equilibrium selectivities within C 4 and C 7 hydrocarbons on both mesoporous solid acids (SiO 2 –Al 2 O 3 , H 3 PW 12 O 40 /SiO 2 ) and the acid forms of various zeolites (BEA, FAU, MFI) via methylation and hydride transfer steps that favor isobutane and triptane formation because of the relative stabilities of ion-pairs at transition states for chains along the preferred growth path. The stabilities of ion-pair transition states increase as acid sites become stronger and energies for charge separation decrease and as van der Waals interactions within pores become stronger, which respectively lead to higher rates on H 3 PW 12 O 40 /SiO 2 and aluminosilicate zeolites than on amorphous SiO 2 –Al 2 O 3 . Solid acids with different strengths and abilities to solvate ion-pairs by confinement differ in selectivity because strength and solvation influence transition states for the hydride transfer, methylation, and isomerization steps to different extents. Stronger acid sites on H 3 PW 12 O 40 /SiO 2 favor isomerization and hydride transfer over methylation; they lead to higher selectivities to n -butane and non-triptane C 7 isomers than the weaker acid sites on BEA, FAU, and mesoporous SiO 2 –Al 2 O 3 . This preference for hydride transfer and isomerization on stronger acids reflects transition states with more diffuse cationic charge, which interact less effectively with conjugate anions than more localized cations at methylation transition states. The latter recover a larger fraction of the energy required to form the ion-pair, and their stabilities are less sensitive to acid strength than for diffuse cations. Large-pore zeolites (BEA, FAU) form triptane with higher selectivity than SiO 2 –Al 2 O 3 because confinement within large pores preferentially solvates the larger transition states for hydride transfer and methylation, which preserve the four-carbon backbone in triptane, over smaller transition states for alkoxide isomerization steps, which disrupt this backbone and cause growth beyond C 7 chains and subsequent facile β-scission to form isobutane. MFI forms isobutane and triptane with much lower selectivity than mesoporous acids or large-pore zeolites, because smaller pores restrict the formation of bimolecular methylation and hydride transfer transition states required for chain growth and termination steps to a greater extent than those for monomolecular alkoxide isomerization. These data and their mechanistic interpretations show that the selective formation of isobutane and triptane from C 1 precursors like DME is favored on all acids as a result of the relative stability of methylation, hydride transfer, and isomerization transition states, but to a lesser extent when small confining voids and stronger acid sites preferentially stabilize monomolecular isomerization transition states. The observed effects of acid strength and confinement on rates and selectivities reflect the more effective stabilization of all ion-pairs on stronger acids and within solvating environments, but a preference for transition states with more diffuse charge on stronger acids and for ion-pairs with the appropriate solvation within voids of molecular dimensions.

Consider the traveling salesman problem (TSP) defined on the complete graph, where the edge costs satisfy the triangle inequality. Let TOUR denote the optimal solution value for the TSP. Two well-known relaxations of the TSP are the subtour elimination problem and the 2-matching problem. If we let SUBT and 2M represent the optimal solution values for these two relaxations, then it has been conjectured that TOUR/SUBT ≤ 4 / 3 , and that 2M/SUBT ≤ 10 / 9 . In this paper, we exploit the structure of certain 1 / 2 -integer solutions for the subtour elimination problem in order to obtain low cost TSP and 2-matching solutions. In particular, we show that for cost functions for which the optimal subtour elimination solution found falls into our classes, the above two conjectures are true. Our proofs are constructive and could be implemented in polynomial time, and thus, for such cost functions, provide a 4/3 (or better) approximation algorithm for the TSP.

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.

Delaminated materials ITQ-2, ITQ-6 and ITQ-18 are very efficient catalysts of zeolitic nature for the synthesis of diamino diphenyl methane (DADPM), the polyamine precursor in the production of MDI for polyurethanes. The exfoliation process results in excellent accessibility of their active sites to reactant molecules as well as fast desorption of products. These catalysts present higher activity and slower rates of deactivation than their corresponding zeolites. Moreover, the topology of the delaminated structure imposes a precise control of the isomer distribution, offering an additional flexibility in the synthesis of DADPM. By optimizing the process conditions it is possible to achieve final DADPM crude under industrial production specifications with ITQ-18. This catalyst represents a real chance for replacing HCl in the industrial production of DADPM., The authors thank Huntsman Polyurethanes and CICYT (MAT2006-14274-C02-01), Project Prometeo from Generalitat Valenciana, Project MULTICAT (Consolider-Ingenio 2010) and Fundacion Areces for financial support.

Rationale and Objectives Diagnostic tests are validated by comparison against a “gold standard” reference test. When the reference test is invasive or expensive, it may not be applied to all patients. This can result in biased estimates of the sensitivity and specificity of the diagnostic test. This type of bias is called “verification bias,” and is a common problem in imaging research. The purpose of our study is to estimate the prevalence of verification bias in the recent radiology literature. Materials and Methods All issues of the American Journal of Roentgenology (AJR), Academic Radiology, Radiology, and European Journal of Radiology (EJR) between November 2006 and October 2009 were reviewed for original research articles mentioning sensitivity or specificity as endpoints. Articles were read to determine whether verification bias was present and searched for author recognition of verification bias in the design. Results During 3 years, these journals published 2969 original research articles. A total of 776 articles used sensitivity or specificity as an outcome. Of these, 211 articles demonstrated potential verification bias. The fraction of articles with potential bias was respectively 36.4%, 23.4%, 29.5%, and 13.4% for AJR, Academic Radiology, Radiology, and EJR. The total fraction of papers with potential bias in which the authors acknowledged this bias was 17.1%. Conclusion Verification bias is a common and frequently unacknowledged source of error in efficacy studies of diagnostic imaging. Bias can often be eliminated by proper study design. When it cannot be eliminated, it should be estimated and acknowledged.

Recent success in cancer immunotherapy has targeted immune checkpoints such as PD-1, PDL-1, and CTLA-4 to enhance the cytotoxic activity of the adaptive T-cell immune response. While the clinical response to these therapies has been dramatic for some, many others have shown partial or even no response highlighting the need for alternative or synergistic approaches that activate innate immunity. Disruption of the interaction between SIRP alpha and CD47, an innate checkpoint inhibitor, using anti-CD47 antibodies, for example, is known to enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages and dendritic cells (DCs) leading to processing and presentation of tumor antigens. Recently, we described AO-176, a next generation anti-CD47 antibody that blocks the CD47/SIRP alpha interaction, induces phagocytosis and causes a direct tumor cell-autonomous death while negligibly binding RBCs. Herein, we characterize the ability of our CD47 antibodies such as AO-176 to induce immunogenic cell death (ICD) and damage-associated molecular patterns (DAMPs) in tumor cells and to potentiate chemotherapy-induced ICD/DAMPs. ICD is a process whereby an agent induces cell surface exposure and release of DAMPs from dying cells which stimulates DCs and adaptive immune responses. Tumor cells were treated in vitro with our CD47 antibodies either alone or in combination with chemotherapeutics followed by assessment of ICD/DAMPs using flow cytometry and biochemical assays. RNAseq was also performed on cells undergoing CD47 antibody mediated ICD/DAMP induction to better understand how CD47 inhibition may regulate ICD. AO-176 and other CD47 antibodies, developed by Arch Oncology, caused mitochondrial stress and loss of outer-membrane integrity, typically observed prior to cells undergoing apoptosis. In addition, CD47 antibody treatment induced a significant ER stress response at the genetic level resulting in the surface exposure of ER chaperone proteins calreticulin, Hsp90, and PDIA3. Concomitantly, our CD47 antibodies increased autophagy and JAK/STAT signaling, which resulted in both ATP and HMGB1 release, respectively. Finally, we demonstrated that in combination, our antibodies potentiated the effects of ICD/DAMP-inducing chemotherapy (e.g., doxorubicin). Here, we describe the unique ability of a specific subset of next generation CD47 antibodies, such as AO-176 to induce ICD/DAMPs. RNAseq analysis of treated cells also revealed alteration of several pathways, including those where DAMPs play a role. In summary, next-generation CD47 antibodies such as AO-176 may provide a novel approach to enhancing the current landscape of checkpoint immunotherapy by enhancing both the innate and adaptive immune responses against tumors. Citation Format: Daniel S. Pereira, Benjamin J. Capoccia, Ronald R. Hiebsch, Michael J. Donio, Alun J. Carter, Robyn J. Puro, W. Casey Wilson, Pamela T. Manning, Robert W. Carr. AO-176, a next-generation anti-CD47 antibody, induces immunogenic cell death [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A147.

The effects of acid identity on CH3OH dehydration are examined here using density functional theory (DFT) estimates of acid strength (as deprotonation energies, DPE) and reaction energies, combined with rate data on Keggin polyoxometalate (POM) clusters and zeolite H-BEA. Measured first-order (kmono) and zero-order (kdimer) CH3OH dehydration rate constants depend exponentially on DPE for POM clusters; the value of kmono depends more strongly on DPE than kdimer does. The chemical significance of these rate parameters and the basis for their dependences on acid strength were established by using DFT to estimate the energies of intermediates and transition states involved in elementary steps that are consistent with measured rate equations. We conclude from this treatment that CH3OH dehydration proceeds via direct reactions of co-adsorbed CH3OH molecules for relevant solid acids and reaction conditions. Methyl cations formed at ion-pair transition states in these direct routes are solvated by H2O and CH3OH more effectively than those in alternate sequential routes involving methoxide formation and subsequent reaction with CH3OH. The stability of ion-pairs, prevalent as intermediates and transition states on solid acids, depends sensitively on DPE because of concomitant correlations between the stability of the conjugate anionic cluster and DPE. The chemical interpretation of kmono and kdimer from mechanism-based rate equations, together with thermochemical cycles of their respective transition state formations, show that similar charge distributions in the intermediate and transition state involved in kdimer cause its weaker dependence on DPE. Values of kmono involve uncharged reactants and the same ion-pair transition state as kdimer; these species sense acid strength differently and cause the larger effects of DPE on kmono. Confinement effects in H-BEA affect the value of kmono because the different sizes and number of molecules in reactants and transition states selectively stabilize the latter; however, they do not influence kdimer, for which reactants and transition states of similar size sense spatial constraints to the same extent. This combination of theory and experiment for solid acids of known structure sheds considerable light on the relative contributions from solvation, electrostatic and van der Waals interactions in stabilizing cationic transition states and provides predictive insights into the relative contributions of parallel routes based on the size and charge distributions of their relevant intermediates and transition states. These findings also demonstrate how the consequences of acid strength on measured turnover rates depend on reaction conditions and their concomitant changes in the chemical significance of the rate parameters measured. Moreover, the complementary use of experiment and theory in resolving mechanistic controversies has given predictive guidance about how rate and equilibrium constants, often inextricably combined as measured rate parameters, individually depend on acid strength based on the magnitude and spatial distributions of charges in reactants, products and transition states involved in relevant elementary steps. The unique relations between kmono, kdimer and DPE developed here for CH3OH dehydration can be applied in practice to assess the acid strength of any solid acid, many of which have unknown structures, preventing reliable calculations of their DPE by theory.

We discuss the effectiveness of integer programming for solving large instances of the independent set problem. Typical LP formulations, even strengthened by clique inequalities, yield poor bounds for this problem. We show that a strong bound can be obtained by the use of the so-called rank inequalities, which generalize the clique inequalities. For some problems the clique inequalities imply the rank inequalities, and then a strong bound is guaranteed already by the simpler formulation.

Neuronal acetylcholine nicotinic receptors (nAChRs) are targets for the development of novel treatments of brain diseases. However, adverse effects (for example, emesis or nausea) associated with high drug maximal exposures or C(max) at nAChRs often hinder the advancement of experimental compounds in clinical trials. Therefore, it is essential to explore the feasibility of maintaining exposures below a predetermined C(max) while sustaining targeted CNS effects. By use of a [¹²³I]5-IA [5-[¹²³I]iodo-3-[2(S)-azetidinylmethoxy]pyridine] displacement SPECT imaging paradigm in nonhuman primates, we compared brain nAChR binding activity elicited by either a bolus injection or by slow infusion of an identical dose of a novel neuronal nicotinic agonist, ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], where the slow infusion scheme was derived from a two-compartment pharmacokinetic modeling designed to limit the C(max). We determined [¹²³I]5-IA displacement using doses of ABT-089 (0.04, 0.4, and 1.0 mg/kg i.v.) that encompassed efficacious drug exposures in nonhuman primates and examined the relationship between ABT-089 displacement ratios and plasma exposures. Our results indicated that calculated displacement ratios were quite similar between the two different dosing regimens despite substantial differences in C(max). In addition, displacement ratios correlated well with drug exposures calculated as the area-under-curve (AUC) of plasma concentration and varied in a dose-dependent manner, suggesting that displacement ratios are driven by the AUC of drug plasma exposure but not C(max). Our data demonstrate the feasibility of predicting plasma exposures using a two-compartment pharmacokinetic model and its potential for optimizing dosing regimens.

Physiologically based pharmacokinetic (PBPK) modeling tools have become an integral part of the modern drug discovery-development process. However, accurate PK prediction of enabling formulations of poorly soluble compounds by applying PBPK modeling has been very limited. This is because current PBPK models rely only on thermodynamic drug solubility inputs (e.g., pH-solubility profile) and give little consideration to the dynamic changes in apparent drug solubility (e.g., supersaturation) that occur during gastrointestinal (GI) transit of an enabling formulation of a water insoluble drug. Moreover, biorepresentative and predictive in vitro tools to measure formulation dependent solubility changes during GI transit remain underdeveloped. In this work, we have developed an in vitro dual pH-dilution method based on rat physiology to estimate the apparent drug concentration in solution along the GI tract during release from solubility enabling formulations. This simple dual pH-dilution method was evaluated using various solubility enabling formulations (i.e., cosolvent solution, amorphous solid dispersions) made using a model early development drug candidate with poor aqueous solubility. The in vitro drug concentration-time profiles from the enabling formulations were used as solubility inputs for PBPK modeling using GastroPlus software. This resulted in excellent predictions of the in vivo oral plasma concentration-time profiles, as compared to using the traditional inputs of thermodynamic pH-solubility profiles. In summary, this work describes a novel in vitro method for facile estimation of formulation dependent GI drug concentration-time profiles and demonstrates the utility of PBPK modeling for oral PK prediction of enabling formulations of poorly soluble drugs.

In March 2007, three prehistoric skeletons were excavated and analysed from Preacher's Cave on the northern aspect of the island of Eleuthera in the Bahama archipelago. The human skeletal remains represent two males and one female dating to AD 800–1300. The first is a female in the 30s with mild osteoarthritis of the joints and spine and several healed fractures who may have been an important community elder. The second is a male in the 20s with Schmorl's nodes who may have been a shaman or even a victim of interpersonal violence. The third is a male in the mid to late 20s also with marginal osteoarthritis of the joints and spine who may have been a ceremonial leader and village headman. The high incidence of carious lesions implies a cariogenic diet possibly rich in starchy foodstuffs or even fructose. The presence of grave goods and plaited mats suggest that at least two individuals may have been of high status. This study emphasises the significance of caves to Lucayan–Taino mythology, cosmology and mortuary practice. Copyright © 2010 John Wiley & Sons, Ltd.

Two pachyosteomorph arthrodires are described from the Upper Devonian of North America, Dunkleosteus raveri sp. nov. and Dunkleosteus amblyodoratus sp. nov. (from the Appalachian and the Michigan basins, respectively). Dunkleosteus raveri sp. nov. is found stratigraphically below the only other species within the Ohio Shale Formation (Famennian), and is characterized by the retention of a primitive dermal ornamentation, and shares with Dunkleosteus terrelli (Newberry, 1873) the possession of articular facets on the parasphenoid. Dunkleosteus amblyodoratus sp. nov. (Kettle Point Formation, Upper Devonian), known only from incomplete nuchal, paranuchal, and parasphenoid plates, also retains dermal tuberculation, and is characterized by tapering articular facets on the parasphenoid. The current study reviews three North American species of Dunkleosteus (Du. terrelli, Du. raveri sp. nov., and Du. amblyodoratus sp. nov.). Formerly, two subgroups were recognized within the Dinichthyidae, the terrelli and herzeri groups, which are shown here to be members of distinct clades. Dinichthys herzeriNewberry, 1868 (the namesake member of the herzeri group) is now the sole member of the family Dinichthyidae comb. nov., and is assigned to the Aspinothoracidi sensuMiles & Dennis, 1979. HeintzichthysWhitley, 1933 and GorgonichthysClaypole, 1892 (additional members of the herzeri group) were previously placed among the aspinothoracid arthrodires. Likewise, Holdenius holdeniDunkle & Bungart, 1942 (the final member of the herzeri group) and Hadrosteus rapaxGross, 1932 are now placed within the Aspinothoracidi. The remaining taxa, formerly assigned to the Dinichthyidae (i.e. DunkleosteusLehman, 1956; EastmanosteusObruchev, 1964; GolshanichthysLelievre, Janvier, & Goujet, 1981; and WestralichthysLong, 1987), are united within the Dunkleosteidae Stensio, 1963. © 2010 The Linnean Society of London, Zoological Journal of the Linnean Society, 2010, 159, 195–222.

The selective removal of methylene diphenylene diisocyanate (MDI) monomers from commercially important MDI-based prepolymers by means of fractionation through a semipermeable polymeric solvent-resistant nanofiltration (SRNF) membrane is demonstrated at laboratory scale.

We consider the problem of designing a contaminant warning system for a municipal water distribution network that uses imperfect sensors, which can generate false-positive and false-negative detections. Although sensor placement optimization methods have been developed for contaminant warning systems, most sensor placement formulations assume perfect sensors, which does not accurately reflect the behavior of real sensor technology. We describe a general exact nonlinear formulation for imperfect sensors and a linear approximation. We consider six general solution strategies, some of which have multiple solution methods. We applied these methods to three test networks, including one with over 10,000 nodes. Our experiments indicate that it is worth deploying a sensor network even when sensors have low detection probability. They also indicate it is worth paying attention to sensor imperfections when placing sensors even when there is a response delay of up to 8 h. The best choice of solution strategy depends upon the user's goals and the problem size. However, for large-scale problems with a moderate number of sensors, using a local search for the linear approximation formulation provides a reasonable-quality solution in a few minutes of computation. Our models assume that sensors can fail via false negatives. Additionally, we discuss ways to model false positives, ways to limit them, and how to trade them off against false negatives. All of our solution methods can handle false positives but our experiments do not explicitly consider them.