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Background This retrospective propensity-matched study investigated the impact of prior percutaneous coronary intervention (PCI) on short-term and long-term survival after coronary artery bypass graft surgery (CABG). Methods A total of 4,634 patients underwent isolated first-time CABG between April 2004 and March 2014. Among these, 424 (9.2%) had PCI. Propensity score analysis yielded 1:1 risk-adjusted matched groups: PCI (330 patients) and non-PCI (330 patients). A Cox proportional hazards model was used among the matched groups to assess the impact of prior PCI among other variables. Kaplan-Meier survival curves were compared at 1, 2, 3, 5, 7, and 10 years using the log-rank test to assess differences in survival. Results In-hospital 30-day mortality was 1.1% (non-PCI) versus 0.9% (prior PCI; p = 0.66). Overall survival at 10 years was 77.5% (non-PCI) versus 82.71% (prior PCI; p = 0.4). Cox regression analysis identified European System for Cardiac Operative Risk Evaluation, nonsinus rhythm, age, pulmonary disease, and urgent surgery as risk factors for increased mortality. Prior PCI was not an independent predictor for mortality (hazard ratio, 0.55; 95% confidence interval, 0.25 to 1.18; p = 0.123). Overall survival in matched cohorts, non-PCI versus prior PCI, was 96.02% versus 97.13% ( p = 0.08) at 1 year, 92.64% versus 96.36% ( p = 0.08) at 3 years, 90.01% versus 93.47% ( p = 0.02) at 5 years, 83.33% versus 90.37% ( p = 0.01) at 7 years, and 73.56% versus 90.27% ( p = 0.004) at 10 years. Conclusions The survival in matched cohorts did not show adverse outcomes with prior PCI at 1, 3, 5, 7, and 10 years. Prior PCI does not adversely impact survival after CABG.

Human onchocerciasis is a serious neglected tropical disease caused by the filarial nematode Onchocerca volvulus that can lead to blindness and chronic disability. Control of the disease relies largely on mass administration of a single drug, and the development of new drugs and vaccines depends on a better knowledge of parasite biology. Here, we describe the chromosomes of O. volvulus and its Wolbachia endosymbiont. We provide the highest-quality sequence assembly for any parasitic nematode to date, giving a glimpse into the evolution of filarial parasite chromosomes and proteomes. This resource was used to investigate gene families with key functions that could be potentially exploited as targets for future drugs. Using metabolic reconstruction of the nematode and its endosymbiont, we identified enzymes that are likely to be essential for O. volvulus viability. In addition, we have generated a list of proteins that could be targeted by Federal-Drug-Agency-approved but repurposed drugs, providing starting points for anti-onchocerciasis drug development.

Leishmania donovani causes visceral leishmaniasis (VL), the second most deadly vector- borne parasitic disease. A recent epidemic in the Indian subcontinent (ISC) caused up to 80% of global VL and over 30,000 deaths per year. Resistance against antimonial drugs has probably been a contributing factor in the persistence of this epidemic. Here we use whole genome sequences from 204 clinical isolates to track the evolution and epidemiology of L. donovani from the ISC. We identify independent radiations that have emerged since a bottleneck coincident with 1960s DDT spraying campaigns. A genetically distinct population frequently resistant to antimonials has a two base-pair insertion in the aquaglyceroporin gene LdAQP1 that prevents the transport of trivalent antimonials. We find evidence of genetic exchange between ISC populations, and show that the mutation in LdAQP1 has spread by recombination. Our results reveal the complexity of L. donovani evolution in the ISC in response to drug treatment., SCOPUS: ar.j, info:eu-repo/semantics/published

Background The immediate administration of oral antiplatelet therapy in the form of aspirin plus a P2Y12 inhibitor is the universally recognised standard of care for patients who present with acute myocardial infarction. Despite strong recommendations for their use, there are a paucity of data describing their onset of action and clinical efficacy during the short time frames from confirmation of diagnosis to reperfusion with primary percutaneous coronary intervention. Objectives To complete a systematic review evaluating the currently available evidence regarding the pharmacokinetic and pharmacodynamic activity of orally administered clopidogrel, prasugrel and ticagrelor during the acute phase of a myocardial infarction in relation to mechanical reperfusion with primary percutaneous coronary angioplasty. Methods We searched PubMed and EMBASE databases up to January 2016 using the terms outlined in our search strategy. Results Twelve papers were included in our final analysis; seven relating to pharmacodynamic studies, one to a pharmacokinetic study and four to pharmacokinetic/pharmacodynamic studies. Conclusion Our results indicate that despite the administration of oral P2Y12 inhibitors including newer more potent agents that should allow for greater and more consistent levels of platelet inhibition, the physiological state of ST segment elevation MI (STEMI) and the co-administration of opioid based analgesia are associated with a reduction in the degree of platelet inhibition achieved following their administration.

Schistosoma mansoni is a parasitic fluke that infects millions of people in the developing world. This study presents the first application of population genomics to S. mansoni based on high-coverage resequencing data from 10 global isolates and an isolate of the closely-related Schistosoma rodhaini, which infects rodents. Using population genetic tests, we document genes under directional and balancing selection in S. mansoni that may facilitate adaptation to the human host. Coalescence modeling reveals the speciation of S. mansoni and S. rodhaini as 107.5–147.6KYA, a period which overlaps with the earliest archaeological evidence for fishing in Africa. Our results indicate that S. mansoni originated in East Africa and experienced a decline in effective population size 20–90KYA, before dispersing across the continent during the Holocene. In addition, we find strong evidence that S. mansoni migrated to the New World with the 16–19th Century Atlantic Slave Trade.

Soil-transmitted nematodes, including the Strongyloides genus, cause one of the most prevalent neglected tropical diseases. Here we compare the genomes of four Strongyloides species, including the human pathogen Strongyloides stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp. KR3021). A significant paralogous expansion of key gene families - families encoding astacin-like and SCP/TAPS proteins - is associated with the evolution of parasitism in this clade. Exploiting the unique Strongyloides life cycle, we compare the transcriptomes of the parasitic and free-living stages and find that these same gene families are upregulated in the parasitic stages, underscoring their role in nematode parasitism.

One of the first genome sequencing projects for a parasitic nematode was that for Haemonchus contortus. The open access data from the Wellcome Trust Sanger Institute provided a valuable early resource for the research community, particularly for the identification of specific genes and genetic markers. Later, a second sequencing project was initiated by the University of Melbourne, and the two draft genome sequences for H. contortus were published back-to-back in 2013. There is a pressing need for long-range genomic information for genetic mapping, population genetics and functional genomic studies, so we are continuing to improve the Wellcome Trust Sanger Institute assembly to provide a finished reference genome for H. contortus. This review describes this process, compares the H. contortus genome assemblies with draft genomes from other members of the strongylid group and discusses future directions for parasite genomics using the H. contortus model.

We sought to assess the relationships between platelet reactivity at different time points, CYP2C19*2 and ABCB1 status and clinical outcomes in patients with acute coronary syndromes (ACS). Anti-platelet response to clopidogrel was studied prospectively using the VerifyNow (VN) P2Y12 assay at the time of angiography and at 30 days post procedure in 151 patients admitted with ACS who underwent percutaneous coronary intervention (PCI). Troponin T levels were measured at angiography and 16-24 hour following PCI. DNA was extracted and the presence of CYP2C19*2 allele and ABCB1 polymorphisms were determined. Adverse cardiovascular and cerebral events (ACCE) were assessed at 12 months. High VN P2Y12 response at angiography was associated with a greater peri-procedural rise in troponin T, but not ACCE. However, VN P2Y12 response measured at 30 days was associated with ACCE (p = 0.017). CYP2C19*2 status was associated with higher VN P2Y12 response at angiography (p 0.0001) and 30 days (p = 0.006) but not ACCE. Near-patient testing for clopidogrel response was associated with subsequent ACCE when performed 30 days following PCI, but not at angiography.

Professor Emeritus J. D. B. (Bruce) Miller died in Canberra, 16 January 2011, in his 89th year. Bruce Miller was without doubt the guiding intelligence of the Department of International Relations ...

The published works of Australian External Affairs Minister R. G. Casey are analysed to illustrate his position in Australian international thought. While intimately associated with various empire causes, he is also shown to have been an advocate of distinct Australian national interests as well as a firm but not uncritical supporter of closer Anglo-American co-operation. He also affirmed realist sentiments, but found some positive value in international institutions. These positions can be reconciled if Casey is interpreted as neither an imperialist nor a nationalist but rather a strong believer in the existence of a transnational British community, a belief characteristic of much conservative Australian international thought in the period between the wars.

[Extract] Geoffrey Blainey has produced a readable introduction to Cook's Endeavour voyage of 1769–1771 that is suitable for non-specialist readers. He acknowledges his debts to J.C. Beaglehole and John Dunmore, but clearly has developed his own considered interpretations of the journals of Cook and Banks. Those journals colour his account, and he quotes from them to good effect.

Following almost 10 years of no reported cases, Guinea worm disease (GWD or dracunculiasis) reemerged in Chad in 2010 with peculiar epidemiological patterns and unprecedented prevalence of infection among non-human hosts, particularly domestic dogs. Since 2014, animal infections with Guinea worms have also been observed in the other three countries with endemic transmission (Ethiopia, Mali, and South Sudan), causing concern and generating interest in the parasites’ true taxonomic identity and population genetics. We present the first extensive population genetic data for Guinea worm, investigating mitochondrial and microsatellite variation in adult female worms from both human and non-human hosts in the four endemic countries to elucidate the origins of Chad’s current outbreak and possible host-specific differences between parasites. Genetic diversity of Chadian Guinea worms was considerably higher than that of the other three countries, even after controlling for sample size through rarefaction, and demographic analyses are consistent with a large, stable parasite population. Genealogical analyses eliminate the other three countries as possible sources of parasite reintroduction into Chad, and sequence divergence and distribution of genetic variation provide no evidence that parasites in human and non-human hosts are separate species or maintain isolated transmission cycles. Both among and within countries, geographic origin appears to have more influence on parasite population structure than host species. Guinea worm infection in non-human hosts has been occasionally reported throughout the history of the disease, particularly when elimination programs appear to be reaching their end goals. However, no previous reports have evaluated molecular support of the parasite species identity. Our data confirm that Guinea worms collected from non-human hosts in the remaining endemic countries of Africa are Dracunculus medinensis and that the same population of worms infects both humans and dogs in Chad. Our genetic data and the epidemiological evidence suggest that transmission in the Chadian context is currently being maintained by canine hosts., Author summary Since the mid-1980’s, when Guinea worm (Dracunculus medinensis) was formally targeted for eradication, the associated national and international efforts to control and eliminate the parasite have been remarkably successful. As of 2017, 16 of the 21 countries with endemic transmission have been certified free of the disease by World Health Organization, and one country (Sudan) is in the pre-certification stage. However, recent and unprecedented prevalence of apparent Guinea worm infection in Chadian dogs has caused concern. That this seemingly sudden emergence in non-human hosts also coincided with an apparent reemergence of infection among humans in Chad after almost 10 years without reported cases raised questions about the population history of Guinea worm in Chad and whether worms from human and non-human hosts were, in fact, the same species. To address these questions, we characterized the genetic variation in Guinea worms collected from various host species and locations in Chad and in the other three endemic countries. Genetic variation was measured in adult female worms using sequence variation of mitochondrial DNA genes and repeat number polymorphism at 23 nuclear microsatellite loci. We found that, regardless of host species, all worms sampled from the remaining endemic countries in Africa are D. medinensis and show no evidence of isolated transmission on the basis of host species.

Summary The early radiation of cetaceans coincides with the origin of their defining ecological and sensory differences [1, 2]. Toothed whales (Odontoceti) evolved echolocation for hunting 36–34 million years ago, whereas baleen whales (Mysticeti) evolved filter feeding and do not echolocate [2]. Echolocation in toothed whales demands exceptional high-frequency hearing [3], and both echolocation and ultrasonic hearing have also evolved independently in bats [4, 5]. The motor protein Prestin that drives the electromotility of the outer hair cells (OHCs) is likely to be especially important in ultrasonic hearing, because it is the vibratory response of OHC to incoming sound waves that confers the enhanced sensitivity and selectivity of the mammalian auditory system [6, 7]. Prestin underwent adaptive change early in mammal evolution [8] and also shows sequence convergence between bats and dolphins [9, 10], as well as within bats [11]. Focusing on whales, we show for the first time that the extent of protein evolution in Prestin can be linked directly to the evolution of high-frequency hearing. Moreover, we find that independent cases of sequence convergence in mammals have involved numerous identical amino acid site replacements. Our findings shed new light on the importance of Prestin in the evolution of mammalian hearing.

The traditional tree of life shows eukaryotes as a distinct lineage of living things, but many studies have suggested that the first eukaryotic cells were chimeric, descended from both Eubacteria (through the mitochondrion) and Archaebacteria. Eukaryote nuclei thus contain genes of both eubacterial and archaebacterial origins, and these genes have different functions within eukaryotic cells. Here we report that archaebacterium-derived genes are significantly more likely to be essential to yeast viability, are more highly expressed, and are significantly more highly connected and more central in the yeast protein interaction network. These findings hold irrespective of whether the genes have an informational or operational function, so that many features of eukaryotic genes with prokaryotic homologs can be explained by their origin, rather than their function. Taken together, our results show that genes of archaebacterial origin are in some senses more important to yeast metabolism than genes of eubacterial origin. This importance reflects these genes’ origin as the ancestral nuclear component of the eukaryotic genome.

Introduction: There is considerable interindividual variation in response to the antiplatelet agent clopidogrel. Hyporesponse predicts negative outcomes in patients presenting with a variety of ischemic cardiac conditions and following intracoronary stent placement. Many tests of clopidogrel activity are time consuming and complex. Short thromboelastography (s-TEG) allows rapid measurement of platelet clopidogrel response. Aims: We initiated this study to investigate the utility of s-TEG in assessing the response to clopidogrel in patients presenting with acute coronary syndromes (ACS) and to compare these results with established clopidogrel monitoring techniques. Methods: Patients admitted with unstable angina (UA) or Non ST elevation myocardial infarction (NSTEMI) undergoing coronary angiography were recruited. After routine loading with clopidogrel, all patients were tested with s-TEG and Accumetrics Verify-Now rapid platelet function analyzer (VN-RPFA). We used the modified TEG technique of measuring area under the curve at 15 min (AUC15), which allows a rapid estimation of antiplatelet response. Vasodilator-stimulated phosphoprotein phosphorylation (VASP) was also tested in a subgroup of patients. Clinical follow-up was obtained at 1 year. s-TEG results were correlated with VN-RPFA and VASP findings. Results: A total of 49 patients (33 male, mean age 63) were recruited and tested with s-TEG and VN-RPFA and a total of 39 patients were also assessed with VASP. s-TEG readings correlated well with VN-RPFA (r2= 0.54, P < 0.0001) and VASP (r2= 0.26, P= 0.001). Conclusion: s-TEG provides timely results which compare to current tests of clopidogrel activity. This technique can also be used to measure a variety of other clotting parameters and as such could develop into a valuable near patient test for the interventional cardiologist.

Despite advances in ST-segment elevation myocardial infarction (STEMI) treatment, a sizeable minority of patients suffer poor outcomes even when treated with timely primary percutaneous coronary intervention (PPCI). More potent P2Y12 inhibition improves clinical outcomes, however oral agents have

Background— The optimal strategy for treating coronary bifurcation lesions remains a subject of debate. With bare-metal stents, single-stent approaches appear to be superior to systematic 2-stent strategies. Drug-eluting stents, however, have low rates of restenosis and might offer improved outcomes with complex stenting techniques. Methods and Results— Patients with significant coronary bifurcation lesions were randomized to either a simple or complex stenting strategy with drug-eluting stents. In the simple strategy, the main vessel was stented, followed by optional kissing balloon dilatation/T-stent. In the complex strategy, both vessels were systematically stented (culotte or crush techniques) with mandatory kissing balloon dilatation. Five hundred patients 64±10 years old were randomized; 77% were male. Eighty-two percent of lesions were true bifurcations (>50% narrowing in both vessels). In the simple group (n=250), 66 patients (26%) had kissing balloons in addition to main-vessel stenting, and 7 (3%) had T stenting. In the complex group (n=250), 89% of culotte (n=75) and 72% of crush (n=169) cases were completed successfully with final kissing balloon inflations. The primary end point (a composite at 9 months of death, myocardial infarction, and target-vessel failure) occurred in 8.0% of the simple group versus 15.2% of the complex group (hazard ratio 2.02, 95% confidence interval 1.17 to 3.47, P =0.009). Myocardial infarction occurred in 3.6% versus 11.2%, respectively ( P =0.001), and in-hospital major adverse cardiovascular events occurred in 2.0% versus 8.0% ( P =0.002), respectively. Procedure duration and x-ray dose favored the simple approach. Conclusions— When coronary bifurcation lesions are treated, a systematic 2-stent technique results in higher rates of in-hospital and 9-month major adverse cardiovascular events. This difference is largely driven by periprocedural myocardial infarction. Procedure duration is longer, and x-ray dose is higher. The provisional technique should remain the preferred strategy in the majority of cases. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00351260.

W.K. Hancock's most important contribution to Australian international relations is his Survey of the Commonwealth, a work informed by a nuanced analysis of the theory of sovereignty sympathetic to the Grotian position of the emerging “English school”. Committed to the contemporary idea of the Commonwealth centred on a shared affirmation of liberty derived from self-rule, Hancock also took seriously but rejected a political economy approach. Though sceptical of some of the grander claims made for the Commonwealth, he did not sufficiently confront the anomalous position of India despite evidence that this question preoccupied him. His conception of the Commonwealth is ultimately derived from the prescription of J.C. Smuts for international organisation and is thus founded on the advocacy of a species of international society as the key to international order.

Depicted as an imperialist by historians, William Harrison Moore, law professor, initiator of international relations teaching in Australia, government expert and League of Nations delegate, is shown to have held a positive view of the role and potential of international institutions, a fact hitherto disregarded yet the key to his thought. He clearly regarded the Empire as making a valuable contribution to the society of states and to Australian interests, but also maintained that the creation of the League had transformed the international system especially in relation to security. In particular, he held that Australia derived undoubted advantages from League membership. Consequently, his internationalism must be seen as the wider context for his imperialist sentiments.

The received view of the development of the international relations discipline in Australia discounts its early history, maintaining that it only came into existence in the 1960s. It was then confined, according to this account, within a realist-rationalist discourse. This article shows that if realism-rationalism is the identifying feature of the discipline in Australia, then many exemplars can be found in the earlier period from the 1920s to the Pacific War. Problems regarding empire, obligations towards the League of Nations, and Australia’s position in the Pacific region were major concerns. Arguments in support of the League, or for an emerging Pacific order, were often couched in rationalist terms; with the increasing international uncertainty of the 1930s, realist arguments became more prominent. There are also some examples of revolutionist theory. However, a major preoccupation across the spectrum of international thinkers was the issue of race and the exclusionary White Australia immigration policy. It is argued that this theme cannot be readily assimilated to realism-rationalism.

In molecular phylogenetic studies, a major aspect of experimental design concerns the choice of markers and taxa. Although previous studies have investigated the phylogenetic performance of different genes and the effectiveness of increasing taxon sampling, their conclusions are partly contradictory, probably because they are highly context specific and dependent on the group of organisms used in each study. Goldman introduced a method for experimental design in phylogenetics based on the expected information to be gained that has barely been used in practice. Here we use this method to explore the phylogenetic utility of mitochondrial (mt) genes, mt genomes, and nuclear rag1 for studies of the systematics of caecilian amphibians, as well as the effect of taxon addition on the stabilization of a controversial branch of the tree. Overall phylogenetic information estimates per gene, specific estimates per branch of the tree, estimates for com- bined (mitogenomic) data sets, and estimates as a hypothetical new taxon is added to different parts of the caecilian tree are calculated and compared. In general, the most informative data sets are those for mt transfer and ribosomal RNA genes. Our results also show at which positions in the caecilian tree the addition of taxa have the greatest potential to increase phylogenetic information with respect to the controversial relationships of Scolecomorphus, Boulengerula, and all other tere- somatan caecilians. These positions are, as intuitively expected, mostly (but not all) adjacent to the controversial branch. Generating whole mitogenomic and rag1 data for additional taxa joining the Scolecomorphus branch may be a more efficient strategy than sequencing a similar amount of additional nucleotides spread across the current caecilian taxon sampling. The methodology employed in this study allows an a priori evaluation and testable predictions of the appropriateness of particular experimental designs to solve specific questions at different levels of the caecilian phylogeny. (Experimental de- sign; Gymnophiona; mitochondrial genes; mitochondrial genome; phylogenetic information; rate of evolution; rag1; taxon sampling.)

2008 marks the 75th anniversary of the Australian Institute of International Affairs (AIIA) as a national organisation. In the context of this anniversary, this paper develops the argument that the...

Introduction Oesophageal adenocarcinoma is an increasingly common diagnosis and cause of death; risk factors include ‘Barrett's epithelium’ (BE). Endoscopic surveillance is most commonly used but is expensive. Other methods of surveillance have been suggested including nonendoscopic balloon cytology, but are handicapped by relying on cytological techniques; hence the need for a partner technology such as a biomarker. From earlier work we know the most commonly expressed oesophageal stress response proteins are SEP 53, SEP70 and anterior gradient-2 (AG-2). We set out to map the expression of these stress response proteins and explore their potential as prototype biomarkers of BE. Methods Patients (n=192) presenting to the endoscopy unit of a large teaching hospital with symptoms of gastro-oesophageal reflux disease or a known BE were recruited, endoscopically examined and the biopsies obtained were examined for heat shock protein expression. Results and discussion Normal controls and those with oesophagitis predominantly expressed SEP 53 (76.9/91.95%) and SEP 70 (79.48/89.65%). Although those with BE expressed AG-2; using this expression as a marker for BE, gives a sensitivity of 65.15% and specificity of 89.68% (positive predictive value of 76.78% and negative predictive value of 84.9%) and in gastro-oesophageal reflux disease a sensitivity of 65.15% and specificity of 90.80% (positive predictive value of 84.31% and negative predictive value of 77.45%). We confirmed that AG-2 is preferentially expressed in BE; suggesting its use would allow a screening tool with specificity of around 90%.

The remarkable high-frequency sensitivity and selectivity of the mammalian auditory system has been attributed to the evolution of mechanical amplification, in which sound waves are amplified by outer hair cells in the cochlea. This process is driven by the recently discovered protein prestin, encoded by the gene Prestin . Echolocating bats use ultrasound for orientation and hunting and possess the highest frequency hearing of all mammals. To test for the involvement of Prestin in the evolution of bat echolocation, we sequenced the coding region in echolocating and nonecholocating species. The resulting putative gene tree showed strong support for a monophyletic assemblage of echolocating species, conflicting with the species phylogeny in which echolocators are paraphyletic. We reject the possibilities that this conflict arises from either gene duplication and loss or relaxed selection in nonecholocating fruit bats. Instead, we hypothesize that the putative gene tree reflects convergence at stretches of functional importance. Convergence is supported by the recovery of the species tree from alignments of hydrophobic transmembrane domains, and the putative gene tree from the intra- and extracellular domains. We also found evidence that Prestin has undergone Darwinian selection associated with the evolution of specialized constant-frequency echolocation, which is characterized by sharp auditory tuning. Our study of a hearing gene in bats strongly implicates Prestin in the evolution of echolocation, and suggests independent evolution of high-frequency hearing in bats. These results highlight the potential problems of extracting phylogenetic signals from functional genes that may be prone to convergence.

This essay considers the Australian approach to Asian regionalism during the tenure of the government led by John Howard. Its main focus is the official Australian policy towards ASEAN, the ASEAN R...

Objective: Laryngopharyngeal reflux (LPR) is a syndrome associated with a constellation of symptoms usually treated by ENT surgeons. It is believed to be caused by the retrograde flow of stomach contents into the laryngopharynx, this being a supra-esophageal manifestation of gastroesophageal reflux disease (GERD). It has been cited that LPR and GERD can be considered separate entities. Our hypothesis was that LPR is a supra-esophageal manifestation of GERD and therefore that patients with GERD should have a degree of symptoms suggestive of LPR because of the reflux of the gastric contents. We examined a population of patients with both upper gastrointestinal endoscopy and symptom-proven GERD and, using a questionnaire, looked at their existing symptoms to help assess the prevalence of LPR. We also looked at whether, with more severe GERD (suggestive of increased gastric content reflux), the degree of symptoms suggestive of LPR would be increased, as would be expected. Methods: A population of patients with endoscopically proven GERD were recruited and divided into groups depending on the severity of their reflux disease. A questionnaire was then administered that examined both LPR and GERD scoring criteria. The relationship between GERD and LPR was then analyzed. Results: We recruited 1,383 subjects with GERD; those with severe GERD had significantly higher LPR scores compared with those with mild (P < .01), moderate (P < .05), or inactive disease (P < .001). Conclusions: The condition of LPR is likely to represent a supra-esophageal manifestation of GERD. This study examined a large number of patients with endoscopically proven GERD and has demonstrated a correlation between the severity of GERD and the prevalence of LPR. LPR and GERD are common and interlinked conditions. The subsequent prevalence of LPR in the population with GERD is therefore likely to be dramatically underestimated.

Most supertree methods proposed to date are essentially ad hoc, rather than designed with particular properties in mind. Although the supertree problem remains difficult, one promising avenue is to develop from better understood consensus methods to the more general supertree setting. Here, we generalize the widely used majority-rule consensus method to the supertree setting. The majority-rule consensus tree is the strict consensus of the median trees under the symmetric-difference metric, so we can generalize the consensus method by generalizing this metric to trees with differing leaf sets. There are two different natural generalizations, based on pruning or grafting leaves to produce comparable trees, and these two generalizations produce two different, but related, majority-rule supertree methods.

Supertree methods (SMs) are techniques for inferring (super)trees from sets of (input) trees. Classical consensus methods are SMs that were designed for the special case where input trees have identical leaf sets. The need for methods that can also combine information from input trees with nonidentical leaf sets has led to many alternative SMs. Some of these SMs are generalizations from conservative consensus methods (strict and semistrict) that do not resolve input tree conflicts (e.g., Gordon, 1986; Goloboff and Pol, 2002). Our focus here is on more liberal SMs, those capable of resolving conflicts among input trees. Liberal SMs comprise the majority of described methods and have been the most used in practice by biologists seeking well-resolved phylogenies. However, today's practitioners are confronted with choosing among a potentially bewildering array of liberal SM(s). Wilkinson et al. (2004) argued that nonarbitrary, rational choice among liberal SMs would best be guided by knowledge of the comparative accuracy of alternative methods. However, there have been few comparisons of accuracy using simulations (Bininda-Emonds and Sanderson, 2001; Chen et al., 2003; Eulenstein et al., 2004; Lapointe and Levasseur, 2004; Ross and Rodrigo, 2004) over a restricted range of conditions. Thus, Wilkinson et al. (2004) also discussed a number of properties that they suggested provide surrogates for accuracy and might therefore be expected of any SM. One of these, that input tree conflicts should be resolved independently of input tree shape, was investigated by Wilkinson et al. (2005a), who used a simple example (Fig. 1) and simulations to demonstrate input tree shape effects with 8 of the 14 methods they investigated, including the widely used matrix representation with parsimony (MRP) of Baum (1992) and Ragan (1992). Here we introduce a class of sub-Pareto properties that we argue constitute particularly weak expectations of how accurate SMs should handle consensus problems. We then use the same example to substantiate and extend results reported in Wilkinson et al. (2004) and to demonstrate that seven of the liberal SMs that are sensitive to input tree shape also lack some seemingly reasonable consensus properties. Lastly, we consider the relevance of these properties to choice and PRELIMINARIES

This paper traces the development of the Six-Party process through to the joint statement by the parties on September 19, 2005, considers the subsequent decision by North Korea to stage a nuclear test in the context of the apparent stasis of the process, and then reviews the international condemnation that was the result of those tests. North Korea's decision to return to the talks is then discussed in light of the policy issues that must be solved if the September 19 principles can be realized in practice.

When the brain has determined the position of a moving object, due to anatomical and processing delays, the object will have already moved to a new location. Given the statistical regularities present in natural motion, the brain may have acquired compensatory mechanisms to minimize the mismatch between the perceived and the real position of a moving object. A well-known visual illusion — the flash lag effect — points towards such a possibility. Although many psychophysical models have been suggested to explain this illusion, their predictions have not been tested at the neural level, particularly in a species of animal known to perceive the illusion. Towards this, we recorded neural responses to flashed and moving bars from primary visual cortex (V1) of awake, fixating macaque monkeys. We found that the response latency to moving bars of varying speed, motion direction and luminance was shorter than that to flashes, in a manner that is consistent with psychophysical results. At the level of V1, our results support the differential latency model positing that flashed and moving bars have different latencies. As we found a neural correlate of the illusion in passively fixating monkeys, our results also suggest that judging the instantaneous position of the moving bar at the time of flash — as required by the postdiction/motion-biasing model — may not be necessary for observing a neural correlate of the illusion. Our results also suggest that the brain may have evolved mechanisms to process moving stimuli faster and closer to real time compared with briefly appearing stationary stimuli.New and NoteworthyWe report several observations in awake macaque V1 that provide support for the differential latency model of the flash lag illusion. We find that the equal latency of flash and moving stimuli as assumed by motion integration/postdiction models does not hold in V1. We show that in macaque V1, motion processing latency depends on stimulus luminance, speed and motion direction in a manner consistent with several psychophysical properties of the flash lag illusion.

Ambitious projects aim to record the activity of ever larger and denser neuronal populations in vivo. Correlations in neural activity measured in such recordings can reveal important aspects of neural circuit organization. However, estimating and interpreting large correlation matrices is statistically challenging. Estimation can be improved by regularization, i.e. by imposing a structure on the estimate. The amount of improvement depends on how closely the assumed structure represents dependencies in the data. Therefore, the selection of the most efficient correlation matrix estimator for a given neural circuit must be determined empirically. Importantly, the identity and structure of the most efficient estimator informs about the types of dominant dependencies governing the system. We sought statistically efficient estimators of neural correlation matrices in recordings from large, dense groups of cortical neurons. Using fast 3D random-access laser scanning microscopy of calcium signals, we recorded the activity of nearly every neuron in volumes 200 μm wide and 100 μm deep (150–350 cells) in mouse visual cortex. We hypothesized that in these densely sampled recordings, the correlation matrix should be best modeled as the combination of a sparse graph of pairwise partial correlations representing local interactions and a low-rank component representing common fluctuations and external inputs. Indeed, in cross-validation tests, the covariance matrix estimator with this structure consistently outperformed other regularized estimators. The sparse component of the estimate defined a graph of interactions. These interactions reflected the physical distances and orientation tuning properties of cells: The density of positive ‘excitatory’ interactions decreased rapidly with geometric distances and with differences in orientation preference whereas negative ‘inhibitory’ interactions were less selective. Because of its superior performance, this ‘sparse+latent’ estimator likely provides a more physiologically relevant representation of the functional connectivity in densely sampled recordings than the sample correlation matrix., Author Summary It is now possible to record the spiking activity of hundreds of neurons at the same time. A meaningful statistical description of the collective activity of these neural populations—their ‘functional connectivity’—is a forefront challenge in neuroscience. We addressed this problem by identifying statistically efficient estimators of correlation matrices of the spiking activity of neural populations. Various underlying processes may reflect differently on the structure of the correlation matrix: Correlations due to common network fluctuations or external inputs are well estimated by low-rank representations, whereas correlations arising from linear interactions between pairs of neurons are well approximated by their pairwise partial correlations. In our data obtained from fast 3D two-photon imaging of calcium signals of large and dense groups of neurons in mouse visual cortex, the best estimation performance was attained by decomposing the correlation matrix into a sparse network of partial correlations (‘interactions’) combined with a low-rank component. The inferred interactions were both positive (‘excitatory’) and negative (‘inhibitory’) and reflected the spatial organization and orientation preferences of the interacting cells. We propose that the most efficient among many estimators provides a more informative picture of the functional connectivity than previous analyses of neural correlations.

A 62-year-old man presented with an anterior ST elevation myocardial infarction and underwent primary percutaneous coronary intervention to an occluded diagonal artery. Following stenting, a type III distal guidewire-induced coronary perforation of the diagonal branch was recognized with extravasation of contrast into the pericardial space. Prolonged balloon inflations proximal to the site of the perforation were unsuccessful. Subcutaneous fat was therefore harvested from the patients upper thigh under local anesthetic and embolized through an Export catheter into the distal diagonal vessel, resulting in the immediate cessation of leak through the site of perforation. We discuss the technical aspects of this technique as well as alternative methods of distal embolization and the potential complications that must be considered.

High entropy alloys offer a new approach in alloy design by combining multiple elements around equiatomic proportions; relatively simple crystal structures may be obtained and promising properties have been reported. However, there is a major challenge to validate complex phase equilibria predictions for such multifold chemistries, and subsequently, to optimize composition within a selected alloy system. In the present case, high-throughput techniques were employed for the synthesis and characterization of thin films of varying composition around the equiatomic FeNiCoCuGa composition. Continuous thin films were deposited by modified molecular beam epitaxy (MBE) technology and annealed in a reducing atmosphere. Subsequently, the thin films were characterized by EDS, SEM and XRD. The results allow isothermal and isochemical sections of the quinary phase diagram to be drawn, revealing domains of three disordered crystalline phases, as well as mapping of their relative concentrations. General trends of the effect of the constituent elements on the phase concentrations and domain of existence can easily be accessed. These results are compared with data obtained from bulk samples.

As national governments scale up mass drug administration (MDA) programs aimed to combat neglected tropical diseases (NTDs), novel selection pressures on these parasites increase. To understand how parasite populations are affected by MDA and how to maximize the success of control programmes, it is imperative for epidemiological, molecular and mathematical modelling approaches to be combined. Modelling of parasite population genetic and genomic structure, particularly of the NTDs, has been limited through the availability of only a few molecular markers to date. The landscape of infectious disease research is being dramatically reshaped by next-generation sequencing technologies and our understanding of how repeated selective pressures are shaping parasite populations is radically altering. Genomics can provide high-resolution data on parasite population structure, and identify how loci may contribute to key phenotypes such as virulence and/or drug resistance. We discuss the incorporation of genetic and genomic data, focussing on the recently sequenced Schistosoma spp., into novel mathematical transmission models to inform our understanding of the impact of MDA and other control methods. We summarize what is known to date, the models that exist and how population genetics has given us an understanding of the effects of MDA on the parasites. We consider how genetic and genomic data have the potential to shape future research, highlighting key areas where data are lacking, and how future molecular epidemiology knowledge can aid understanding of transmission dynamics and the effects of MDA, ultimately informing public health policy makers of the best interventions for NTDs.

A supertree is a phylogeny formed by combining information from disparate phylogenetic trees. Supertree methods have been particularly used for constructing large phylogenies from previously published trees and there is a growing literature using supertree methods for phylogenetic inference in macroevolutionary studies (e.g., Davies et al., 2004; Grotkopp et al., 2004; Salamin and Davies, 2004). This empirical supertree work has mostly used matrix representation with parsimony (standard MRP; Baum, 1992; Ragan, 1992) in which optimal supertrees are found by parsimony analysis of a matrix encoding the full splits of the input trees. A major concern with standard MRP (and some other) supertrees is that they can display relationships that seem to lack evidential support from the input trees, either individually or jointly (Bininda-Emonds and Bryant, 1998; Pisani and Wilkinson, 2002; Wilkinson et al., 2004b). This has prompted the development of measures of support that attempt to distinguish supported and unsupported relationships in supertrees (Bininda-Emonds, 2003; Wilkinson et al., 2005b). A standard means of analyzing the distribution of support across a phylogenetic hypothesis is to deconstruct a tree into the less complex relationships that the tree entails. For example, bootstrap proportions are typically reported for a set of full splits (clades on rooted trees) on the taxa of interest, and a number of other measures on trees are focused at identifying clade-based support (e.g., Bremer, 1994; Larget and Simon, 1999). In the supetree context, clades must be supported by input trees rather than by characters, and a supertree and the input trees generally have different leaf sets, so that a supertree clade may not be displayed by any input tree. This has left scope for ambiguity as to how to identify and quantify support in the supertree context (Bininda-Emonds, 2003; Wilkinson et al., 2005b). One solution is to seek some kind of soft, or reduced, support, in which input clades that are compatible with or entailed by supertree clades are seen as providing some level of support for these supertree relationships. Previous work has two important limitations. It focuses only on support (or lack of support) for supertree clades (components, full splits), ignoring support for less inclusive relationships like partial splits, triplets, or nestings (Wilkinson, 1994). We show that a more sensitive measure of support, focusing on lower-level relationships, may give a different picture of which supertree relationships are supported and unsupported. In fact, a supertree clade can appear unsupported despite all the triplets it implies being supported. As noted by Wilkinson et al. (2005b), “input trees may jointly entail, and thus strictly support, novel relationships that are not strictly supported by any single input tree.” The second limitation of previous work is that it relies on pairwise comparisons between each input tree and the supertree and consequently does not fully account for support jointly entailed by combinations of input trees. As the primary use of supertree methods is to combine information from a set of input trees, being able to identify this kind of support seems particularly important. Some authors have claimed total-evidence-like properties of signal enhancement for supertree methods (Bininda-Emonds et al., 1999), but novel relationships displayed by a supertree (relationships not present on any of the input trees) are worrying if they are not implied by combinations of the input trees (see Pisani and Wilkinson, 2002). Focusing exclusively on a rooted supertree and rooted input trees, we present a method for examining the support for triplets in a rooted supertree that can be naturally extended to identify combined support for supertree relationships, based on inference rules for triplets. We show that considering this combined support can reveal support for additional supertree relationships and so better diagnose unsupported relationships.

Ambrose Monell Cryo Collection Humbold State University Louisiana State University Museum of Southwestern Biology Museum of the North, Alaska Museum of Vertebrate Zoology, Berkeley Smithsonian National Museum of Natural History South Australian Museum Texas A&M The Field Museum, Chicago The Natural History Museum, London University of Washington, Burke http://research.amnh.org/amcc/ http://www.humboldt.edU/~bsa2/collection.html#tissues http://www.museum.lsu.edu/LSUMNS/Museum/NatSci/tissues.html http://nix.msb.unm.edu/test/queryform.php http://www.uaf.edu/museum/af/ http://www.mip.berkeley.edu/mvz/collections/TissueCollection.html http://www.mnh.si.edu/rc/ http://www.samuseum.sa.gov.au/orig/ebu.htm http://wfscnet.tamu.edu/tcwc/tissue_collection.htm http : // www. fieldmuseum. org / research.collections / default.htm http://www.nhm.ac.uk/zoology/zoocollect.html http://www.washington.edu/burkemuseum/tissuepolicy.html

Using a simple example and simulations, we explore the impact of input tree shape upon a broad range of supertree methods. We find that input tree shape can affect how conflict is resolved by several supertree methods and that input tree shape effects may be substantial. Standard and irreversible matrix representation with parsimony (MRP), MinFlip, duplication-only Gene Tree Parsimony (GTP), and an implementation of the average consensus method have a tendency to resolve conflict in favor of relationships in unbalanced trees. Purvis MRP and the average dendrogram method appear to have an opposite tendency. Biases with respect to tree shape are correlated with objective functions that are based upon unusual asymmetric tree-to-tree distance or fit measures. Split, quartet, and triplet fit, most similar supertree, and MinCut methods (provided the latter are interpreted as Adams consensus-like supertrees) are not revealed to have any bias with respect to tree shape by our example, but whether this holds more generally is an open problem. Future development and evaluation of supertree methods should consider explicitly the undesirable biases and other properties that we highlight. In the meantime, use of a single, arbitrarily chosen supertree method is discouraged. Use of multiple methods and/or weighting schemes may allow practical assessment of the extent to which inferences from real data depend upon methodological biases with respect to input tree shape or size.

As a US-led coalition operation designed to obstruct weapons proliferation, the Proliferation Security Initiative (PSI) is especially applicable to North Korea. Though practical measures have been developed to implement the interdiction of seaborne weapons shipments in particular, the PSI has yet to be rendered consistent with the international legal regime supporting free navigation of the high seas. Nor has it attracted specific United Nations support. A review of the 1962 ‘quarantine’ of Cuba demonstrates that in the absence of a more restrictive approach towards Pyongyang and conclusive evidence that North Korean weapons capability poses a current threat to the United States, the appellation ‘Cuba Lite’ is not inappropriate. Furthermore, in the context of multilateral diplomacy intended to persuade North Korea to relinquish its nuclear weapons programs in exchange for security guarantees, the PSI may be interpreted as pressuring Pyongyang and thus may not be perceived – even by PSI coalition partners – as consistent with that diplomacy.

Independent East Timor, with U.N. support until May 2005, is straining to cope with problems of institution building and development. The vital issue of hydrocarbon revenues remains unresolved because of a territorial dispute with Australia and problems with the structures proposed to manage those resources.

Alison Broinowski, 2003. About Face. Asian Accounts of Australia (Carlton North: Scribe) pp. xiv+288. Rawdon Dalrymple, 2003. Continental Drift. Australia's Search for a Regional Identity (Aldersho...

In 2002 the inclusion of North Korea by the Bush administration within the 'axis of evil' portended a break from the Clinton policy of engagement. Despite the apparent inconsistencies of this categorisation, North Korea's undoubted possession of some weapons of mass destruction capability seemed to make it a possible target for US containment if not preemption. However, Pyongyang's chief motive in such weapons development might actually be to guarantee regime survival. The revelation that North Korea had been developing a covert uranium enrichment program led US policymakers in the Bush administration to contemplate a policy of quarantine and containment. The wider policy community is divided on the question of whether Pyongyang was seeking a new bargain with the US, or whether this program was intended to produce a deterrent from possible US attack. These alternatives prescribe, respectively, a new negotiating approach or a strategy designed to dissuade. But the actual policy choice hinges on the outcome...