Towards better management of Australia’s shark fishery: genetic analyses reveal unexpected ratios of cryptic blacktip species Carcharhinus tilstoni and C. limbatus

The common blacktip shark (Carcharhinus limbatus) and the Australian blacktip shark (C. tilstoni) are morphologically similar species that co-occur in subtropical and tropical Australia. In striking contrast to what has been previously reported, we demonstrate that the common blacktip shark is not rare in northern Australia but occurs in approximately equal frequencies with the Australian blacktip shark. Management of shark resources in northern Australia needs to take account of this new information. Species identification was performed using nucleotide sequences of the control, NADH dehydrogenase subunit 4 (ND4) and cytochrome oxidase I (COI) regions in the mitochondrial genome. The proportion of overall genetic variation (FST) between the two species was small (0.042, P < 0.01) based on allele frequencies at five microsatellite loci. We confirm that a third blacktip species (C. amblyrhynchoides, graceful shark) is closely related to C. tilstoni and C. limbatus and can be distinguished from them on the basis of mtDNA sequences from two gene regions. The Australian blacktip shark (C. tilstoni) was not encountered among 20 samples from central Indonesia that were later confirmed to be common blacktip and graceful sharks. Fisheries regulators urgently need new information on life history, population structure and morphological characters for species identification of blacktip shark species in Australia.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata

Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 x 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Devolution of forest-related rights: Comparative analyses of six developing countries

The study focused on the different ways that forest-related rights can be devolved to the local level according to the current legal frameworks in Laos, Nepal, Vietnam, Kenya, Mozambique and Tanzania. The eleven case studies represented the main ways in which forest-related rights can be devolved to communities or households in these countries. The objectives of this study were to 1) analyse the contents and extent of forest-related rights that can be devolved to the local level, 2) develop an empirical typology that represents the main types of devolution, and 3) compare the cases against a theoretical ideal type to assess in what way and to what extent the cases are similar to or differ from the theoretical construct. Fuzzy set theory, Qualitative Comparative Analysis and ideal type analysis were used in analysing the case studies and in developing an empirical typology. The theoretical framework, which guided data collection and analyses, was based on institutional economics and theories on property rights, common pool resources and collective action. On the basis of the theoretical and empirical knowledge, the most important attributes of rights were defined as use rights, management rights, exclusion rights, transfer rights and the duration and security of the rights. The ideal type was defined as one where local actors have been devolved comprehensive use rights, extensive management rights, rights to exclude others from the resource and rights to transfer these rights. In addition, the rights are to be secure and held perpetually. The ideal type was used to structure the analysis and as a tool against which the cases were analysed. The contents, extent and duration of the devolved rights varied greatly. In general, the results show that devolution has mainly meant the transfer of use rights to the local level, and has not really changed the overall state control over forest resources. In most cases the right holders participate, or have a limited role in the decision making regarding the harvesting and management of the resource. There was a clear tendency to devolve the rights to enforce rules and to monitor resource use and condition more extensively than the powers to decide on the management and development of the resource. The empirical typology of the cases differentiated between five different types of devolution. The types can be characterised by the devolution of 1) restricted use and control rights, 2) extensive use rights but restricted control rights, 3) extensive rights, 4) insecure, short term use and restricted control rights, and 5) insecure extensive rights. Overall, the case studies conformity to the ideal type was very low: only two cases were similar to the ideal type, all other cases differed considerably from the ideal type. The restricted management rights were the most common reason for the low conformity to the ideal type (eight cases). In three cases, the short term of the rights, restricted transfer rights, restricted use rights or restricted exclusion rights were the reason or one of the reasons for the low conformity to the ideal type. In two cases the rights were not secure.

Exclusion of angiotensinogen gene in molecular basis of human hypertension: Sibpair linkage and association analyses in Australian anglo-caucasians

Linkage with essential hypertension has been claimed for a microsatellite marker near the angiotensinogen gene (AGT; chromosome 1q42), as has association for the AGT variants M235T, G(-6)A and A(-20)C. To more rigorously evaluate AGT as a candidate gene for hypertension we performed sibpair analysis with multiple microsatellite markers surrounding this locus and using more sophisticated analysis programs. We also performed an association study of the AGT variants in unrelated subjects with a strong family history (two affected parents). For the linkage study, single and multiplex polymerase chain reaction (PCRs) and automated genescan analysis were conducted on DNA from 175 Australian Anglo-Celtic Caucasian hypertensives for the following markers: D1S2880-(2.1 cM)-D1S213-(2.8 cM)-D1S251-(6.5 cM)-AGT-(2.0 cM) -D1S235. Statistical evaluation of genotype data by nonparametric methods resulted in the following scores: Single-point analysis - SPLINK, P > 0.18; APM method, P > 0.25; ASPEX, MLOD < 0.28; SIB-PAIR, P > 0. 24; Multipoint analysis - MAPMAKER/SIBS, MLOD < 0.24; GENEHUNTER, P > 0.35. Exclusion scores of Lod -4.1 to -5.1 were obtained for these markers using MAPMAKER/SIBS for a lambda(s) of 1.6. The association study of G(-6)A, A(-20)C and M235T variants in 111 hypertensives with strong family history and 190 normotensives with no family history showed significant linkage disequilibrium between particular haplotypes, but we could find no association with hypertension. The present study therefore excludes AGT in the etiology of hypertension, at least in the population of Australian Anglo-Celtic Caucasians studied.

Structural analyses of (1->3),(1->4)-β-D-glucan of oats and barley

The structures of (1→3),(1→4)-β-D-glucans of oat bran, whole-grain oats and barley and processed foods were analysed. Various methods of hydrolysis of β-glucan, the content of insoluble fibre of whole grains of oats and barley and the solution behaviour of oat and barley β-glucans were studied. The isolated soluble β-glucans of oat bran and whole-grain oats and barley were hydrolysed with lichenase, an enzyme specific for (1→3),(1→4)-β-D-β-glucans. The amounts of oligosaccharides produced from bran were analysed with capillary electrophoresis and those from whole-grains with high-performance anion-exchange chromatography with pulse-amperometric detection. The main products were 3-O-β-cellobiosyl-D-glucose and 3-O-β-cellotriosyl-D-glucose, the oligosaccharides which have a degree of polymerisation denoted by DP3 and DP4. Small differences were detected between soluble and insoluble β-glucans and also between β-glucans of oats and barley. These differences can only be seen in the DP3:DP4 ratio which was higher for barley than for oat and also higher for insoluble than for soluble β-glucan. A greater proportion of barley β-glucan remained insoluble than of oat β-glucan. The molar masses of soluble β-glucans of oats and barley were the same as were those of insoluble β-glucans of oats and barley. To analyse the effects of cooking, baking, fermentation and drying, β-glucan was isolated from porridge, bread and fermentate and also from their starting materials. More β-glucan was released after cooking and less after baking. Drying decreased the extractability for bread and fermentate but increased it for porridge. Different hydrolysis methods of β-glucan were compared. Acid hydrolysis and the modified AOAC method gave similar results. The results of hydrolysis with lichenase gave higher recoveries than the other two. The combination of lichenase hydrolysis and high-performance anion-exchange chromatography with pulse-amperometric detection was found best for the analysis of β-glucan content. The content of insoluble fibre was higher for barley than for oats and the amount of β-glucan in the insoluble fibre fraction was higher for oats than for barley. The flow properties of both water and aqueous cuoxam solutions of oat and barley β-glucans were studied. Shear thinning was stronger for the water solutions of oat β-glucan than for barley β-glucan. In aqueous cuoxam shear thinning was not observed at the same concentration as in water but only with high concentration solutions. Then the viscosity of barley β-glucan was slightly higher than that of oat β-glucan. The oscillatory measurements showed that the crossover point of the G´ and G´´ curves was much lower for barley β-glucan than for oat β-glucan indicating a higher tendency towards solid-like behaviour for barley β-glucan than for oat β-glucan.

The need for cost-effectiveness analyses of antimicrobial stewardship programmes: A structured review

The cost effectiveness of antimicrobial stewardship (AMS) programmes was reviewed in hospital settings of Organisation for Economic Co-operation and Development (OECD) countries, and limited to adult patient populations. In each of the 36 studies, the type of AMS strategy and the clinical and cost outcomes were evaluated. The main AMS strategy implemented was prospective audit with intervention and feedback (PAIF), followed by the use of rapid technology, including rapid polymerase chain reaction (PCR)-based methods and matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) technology, for the treatment of bloodstream infections. All but one of the 36 studies reported that AMS resulted in a reduction in pharmacy expenditure. Among 27 studies measuring changes to health outcomes, either no change was reported post-AMS, or the additional benefits achieved from these outcomes were not quantified. Only two studies performed a full economic evaluation: one on a PAIF-based AMS intervention; and the other on use of rapid technology for the selection of appropriate treatment for serious Staphylococcus aureus infections. Both studies found the interventions to be cost effective. AMS programmes achieved a reduction in pharmacy expenditure, but there was a lack of consistency in the reported cost outcomes making it difficult to compare between interventions. A failure to capture complete costs in terms of resource use makes it difficult to determine the true cost of these interventions. There is an urgent need for full economic evaluations that compare relative changes both in clinical and cost outcomes to enable identification of the most cost-effective AMS strategies in hospitals.

Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

Meta-analyses of the determinants and outcomes of belief in climate change

Recent growth in the number of studies examining belief in climate change is a positive development, but presents an ironic challenge in that it can be difficult for academics, practitioners and policy makers to keep pace. As a response to this challenge, we report on a meta-analysis of the correlates of belief in climate change. Twenty-seven variables were examined by synthesizing 25 polls and 171 academic studies across 56 nations. Two broad conclusions emerged. First, many intuitively appealing variables (such as education, sex, subjective knowledge, and experience of extreme weather events) were overshadowed in predictive power by values, ideologies, worldviews and political orientation. Second, climate change beliefs have only a small to moderate effect on the extent to which people are willing to act in climate-friendly ways. Implications for converting sceptics to the climate change cause—and for converting believers’ intentions into action—are discussed.