Direct and indirect effects of screening for Chlamydia trachomatis on the prevention of pelvic inflammatory disease: a mathematical modeling study

BACKGROUND Pelvic inflammatory disease (PID) results from the ascending spread of microorganisms, including Chlamydia trachomatis, to the upper genital tract. Screening could improve outcomes by identifying and treating chlamydial infections before they progress to PID (direct effect) or by reducing chlamydia transmission (indirect effect). METHODS We developed a compartmental model that represents a hypothetical heterosexual population and explicitly incorporates progression from chlamydia to clinical PID. Chlamydia screening was introduced, with coverage increasing each year for 10 years. We estimated the separate contributions of the direct and indirect effects of screening on PID cases prevented per 100,000 women. We explored the influence of varying the time point at which clinical PID could occur and of increasing the risk of PID after repeated chlamydial infections. RESULTS The probability of PID at baseline was 3.1% by age 25 years. After 5 years, the intervention scenario had prevented 187 PID cases per 100,000 women and after 10 years 956 PID cases per 100,000 women. At the start of screening, most PID cases were prevented by the direct effect. The indirect effect produced a small net increase in PID cases, which was outweighed by the effect of reduced chlamydia transmission after 2.2 years. The later that progression to PID occurs, the greater the contribution of the direct effect. Increasing the risk of PID with repeated chlamydial infection increases the number of PID cases prevented by screening. CONCLUSIONS This study shows the separate roles of direct and indirect PID prevention and potential harms, which cannot be demonstrated in observational studies.

Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o- -subunit interaction with Cav1 channels

Voltage-dependent calcium channels (VDCCs) serve a wide range of physiological functions and their activity is modulated by different neurotransmitter systems. GABAergic inhibition of VDCCs in neurons has an important impact in controlling transmitter release, neuronal plasticity, gene expression and neuronal excitability. We investigated the molecular signalling mechanisms by which GABAB receptors inhibit calcium-mediated electrogenesis (Ca2+ spikes) in the distal apical dendrite of cortical layer 5 pyramidal neurons. Ca2+ spikes are the basis of coincidence detection and signal amplification of distal tuft synaptic inputs characteristic for the computational function of cortical pyramidal neurons. By combining dendritic whole-cell recordings with two-photon fluorescence Ca2+ imaging we found that all subtypes of VDCCs were present in the Ca2+ spike initiation zone, but that they contribute differently to the initiation and sustaining of dendritic Ca2+ spikes. Particularly, Cav1 VDCCs are the most abundant VDCC present in this dendritic compartment and they generated the sustained plateau potential characteristic for the Ca2+ spike. Activation of GABAB receptors specifically inhibited Cav1 channels. This inhibition of L-type Ca2+ currents was transiently relieved by strong depolarization but did not depend on protein kinase activity. Therefore, our findings suggest a novel membrane-delimited interaction of the Gi/o-βγ-subunit with Cav1 channels identifying this mechanism as the general pathway of GABAB receptor-mediated inhibition of VDCCs. Furthermore, the characterization of the contribution of the different VDCCs to the generation of the Ca2+ spike provides new insights into the molecular mechanism of dendritic computation.

Using the contribution matrix to evaluate complex study limitations in a network meta-analysis: a case study of bipolar maintenance pharmacotherapy review.

BACKGROUND Limitations in the primary studies constitute one important factor to be considered in the grading of recommendations assessment, development, and evaluation (GRADE) system of rating quality of evidence. However, in the network meta-analysis (NMA), such evaluation poses a special challenge because each network estimate receives different amounts of contributions from various studies via direct as well as indirect routes and because some biases have directions whose repercussion in the network can be complicated. FINDINGS In this report we use the NMA of maintenance pharmacotherapy of bipolar disorder (17 interventions, 33 studies) and demonstrate how to quantitatively evaluate the impact of study limitations using netweight, a STATA command for NMA. For each network estimate, the percentage of contributions from direct comparisons at high, moderate or low risk of bias were quantified, respectively. This method has proven flexible enough to accommodate complex biases with direction, such as the one due to the enrichment design seen in some trials of bipolar maintenance pharmacotherapy. CONCLUSIONS Using netweight, therefore, we can evaluate in a transparent and quantitative manner how study limitations of individual studies in the NMA impact on the quality of evidence of each network estimate, even when such limitations have clear directions.

Global distributions of Phaeocystis sp. abundance and biomass - Gridded data product (NetCDF) - Contribution to the MAREDAT World Ocean Atlas of Plankton Functional Types

The planktonic haptophyte Phaeocystis has been suggested to play a fundamental role in the global biogeochemical cycling of carbon and sulphur, but little is known about its global biomass distribution. We have collected global microscopy data of the genus Phaeocystis and converted abundance data to carbon biomass using species-specific carbon conversion factors. Microscopic counts of single-celled and colonial Phaeocystis were obtained both through the mining of online databases and by accepting direct submissions (both published and unpublished) from Phaeocystis specialists. We recorded abundance data from a total of 1595 depth-resolved stations sampled between 1955-2009. The quality-controlled dataset includes 5057 counts of individual Phaeocystis cells resolved to species level and information regarding life-stages from 3526 samples. 83% of stations were located in the Northern Hemisphere while 17% were located in the Southern Hemisphere. Most data were located in the latitude range of 50-70° N. While the seasonal distribution of Northern Hemisphere data was well-balanced, Southern Hemisphere data was biased towards summer months. Mean species- and form-specific cell diameters were determined from previously published studies. Cell diameters were used to calculate the cellular biovolume of Phaeocystis cells, assuming spherical geometry. Cell biomass was calculated using a carbon conversion factor for Prymnesiophytes (Menden-Deuer and Lessard, 2000). For colonies, the number of cells per colony was derived from the colony volume. Cell numbers were then converted to carbon concentrations. An estimation of colonial mucus carbon was included a posteriori, assuming a mean colony size for each species. Carbon content per cell ranged from 9 pg (single-celled Phaeocystis antarctica) to 29 pg (colonial Phaeocystis globosa). Non-zero Phaeocystis cell biomasses (without mucus carbon) range from 2.9 - 10?5 µg l-1 to 5.4 - 103 µg l-1, with a mean of 45.7 µg l-1 and a median of 3.0 µg l-1. Highest biomasses occur in the Southern Ocean below 70° S (up to 783.9 µg l-1), and in the North Atlantic around 50° N (up to 5.4 - 103 µg l-1).

Comparative exergy analysis of direct alcohol fuel cells using fuel mixtures

Within the last years there has been increasing interest in direct liquid fuel cells as power sources for portable devices and, in the future, power plants for electric vehicles and other transport media as ships will join those applications. Methanol is considerably more convenient and easy to use than gaseous hydrogen and a considerable work is devoted to the development of direct methanol fuel cells. But ethanol has much lower toxicity and from an ecological viewpoint ethanol is exceptional among all other types of fuel as is the only chemical fuel in renewable supply. The aim of this study is to investigate the possibility of using direct alcohol fuel cells fed with alcohol mixtures. For this purpose, a comparative exergy analysis of a direct alcohol fuel cell fed with alcohol mixtures against the same fuel cell fed with single alcohols is performed. The exergetic efficiency and the exergy loss and destruction are calculated and compared in each case. When alcohol mixtures are fed to the fuel cell, the contribution of each fuel to the fuel cell performance is weighted attending to their relative proportion in the aqueous solution. The optimum alcohol composition for methanol/ethanol mixtures has been determined.

A contribution to the optimal numbering of tree structures

This paper develops an automatic procedure for the optimal numbering of members and nodes in tree structures. With it the stiffness matrix is optimally conditioned either if a direct solution algorithm or a frontal one is used to solve the system of equations. In spite of its effectiveness, the procedure is strikingly simple and so is the computer program shown below.

Direct isolation of human BRCA2 gene by transformation-associated recombination in yeast

Mutant forms of the BRCA2 gene contribute significantly to hereditary breast cancer. Isolation of the normal and mutant forms of the BRCA2 gene with its natural promoter would greatly facilitate analysis of the gene and its contribution to breast cancer. We have accomplished the direct isolation of the 90-kb gene from total human DNA by transformation-associated recombination in yeast using a small amount of 5′ and 3′ BRCA2 sequence information. Because the entire isolation procedure of a single chromosomal gene could be accomplished in approximately 2 weeks, the transformation-associated recombination cloning approach is readily applicable to studies of chromosome alterations and human genetic diseases.

Effect of genetic background on the contribution of New Zealand Black loci to autoimmune lupus nephritis

Autoimmune diseases such as systemic lupus erythematosus are complex genetic traits with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes. Studies of animal models of lupus have provided important insight into the immunopathogenesis of disease, and genetic analyses of these models overcome certain obstacles encountered when studying human patients. Genome-wide scans of different genetic crosses have been used to map several disease-linked loci in New Zealand hybrid mice. Although some consensus exists among studies mapping the New Zealand Black (NZB) and New Zealand White (NZW) loci that contribute to lupus-like disease, considerable variability is also apparent. A variable in these studies is the genetic background of the non-autoimmune strain, which could influence genetic contributions from the affected strain. A direct examination of this question was undertaken in the present study by mapping NZB nephritis-linked loci in backcrosses involving different non-autoimmune backgrounds. In a backcross with MHC-congenic C57BL/6J mice, H2z appeared to be the strongest genetic determinant of severe lupus nephritis, whereas in a backcross with congenic BALB/cJ mice, H2z showed no influence on disease expression. NZB loci on chromosomes 1, 4, 11, and 14 appeared to segregate with disease in the BALB/cJ cross, but only the influence of the chromosome 1 locus spanned both crosses and showed linkage with disease when all mice were considered. Thus, the results indicate that contributions from disease-susceptibility loci, including MHC, may vary markedly depending on the non-autoimmune strain used in a backcross analysis. These studies provide insight into variables that affect genetic heterogeneity and add an important dimension of complexity for linkage analyses of human autoimmune disease.

Critical contribution of beta chain residue 57 in peptide binding ability of both HLA-DR and -DQ molecules.

Position 57 in the beta chain of HLA class II molecules maintains an Asp/non-Asp dimorphism that has been conserved through evolution and is implicated in susceptibility to some autoimmune diseases. The latter effect may be due to the influence of this residue on the ability of class II alleles to bind specific pathogenic peptides. We utilized highly homologous pairs of both DR and DQ alleles that varied at residue 57 to investigate the impact of this dimorphism on binding of model peptides. Using a direct binding assay of biotinylated peptides on whole cells expressing the desired alleles, we report several peptides that bind differentially to the allele pairs depending on the presence or absence of Asp at position 57. Peptides with negatively charged residues at anchor position 9 bind well to alleles not containing Asp at position 57 in the beta chain but cannot bind well to homologous Asp-positive alleles. By changing the peptides at the single residue predicted to interact with this position 57, we demonstrate a drastically altered or reversed pattern of binding. Ala analog peptides confirm these interactions and identify a limited set of interaction sites between the bound peptides and the class II molecules. Clarification of the impact of specific class II polymorphisms on generating unique allele-specific peptide binding "repertoires" will aid in our understanding of the development of specific immune responses and HLA-associated diseases.

Who decides? Resolving failed banks in a European framework. Bruegel Policy Contribution 2013/16, 29 November 2013

As the basis for a European regime for resolving failing and failed banks, the European Commission has proposed the Bank Resolution and Recovery Directive (BRRD) and a regulation establishing a European Single Resolution Mechanism (SRM) and a Single Bank Resolution Fund (SBRF). There is a debate about which parts of the proposed SRM-SBRF to add to the BRRD. The BRRD sets out a resolution toolkit that can be used by national resolution authorities. The SRM would involve European institutions more at the expense of national resolution authorities. This change could affect resolution outcomes. Domestic resolution authorities might be more generous than supranational authorities in providing assistance to banks. A supranational approach might be more effective in minimising costs for taxpayers. But regardless of the final design, more attention is needed to ensure that resolution authorities are politically independent from governments. When public support is provided to failed institutions it should come from a bankfunded resolution fund. This would reduce taxpayers’ direct costs, and would make banks less likely to take risks and advocate for bailouts.

Asset-backed securities: The key to unlocking Europe's credit markets? Bruegel Policy Contribution 2014/07, 24 July 2014

The European market for asset-backed securities (ABS) has all but closed for business since the start of the economic and financial crisis. ABS (see Box 1) were in fact the first financial assets hit at the onset of the crisis in 2008. The subprime mortgage meltdown caused a deterioration in the quality of collateral in the ABS market in the United States, which in turn dried up overall liquidity because ABS AAA notes were popular collateral for inter-bank lending. The lack of demand for these products, together with the Great Recession in 2009, had a considerable negative impact on the European ABS market. The post-crisis regulatory environment has further undermined the market. The practice of slicing and dicing of loans into ABS packages was blamed for starting and spreading the crisis through the global financial system. Regulation in the post-crisis context has thus been relatively unfavourable to these types of instruments, with heightened capital requirements now necessary for the issuance of new ABS products. And yet policymakers have recently underlined the need to revitalise the ABS market as a tool to improve credit market conditions in the euro area and to enhance transmission of monetary policy. In particular, the European Central Bank and the Bank of England have jointly emphasised that: “a market for prudently designed ABS has the potential to improve the efficiency of resource allocation in the economy and to allow for better risk sharing... by transforming relatively illiquid assets into more liquid securities. These can then be sold to investors thereby allowing originators to obtain funding and, potentially, transfer part of the underlying risk, while investors in such securities can diversify their portfolios... . This can lead to lower costs of capital, higher economic growth and a broader distribution of risk” (ECB and Bank of England, 2014a). In addition, consideration has started to be given to the extent to which ABS products could become the target of explicit monetary policy operations, a line of action proposed by Claeys et al (2014). The ECB has officially announced the start of preparatory work related to possible outright purchases of selected ABS1. In this paper we discuss how a revamped market for corporate loans securitised via ABS products, and how use of ABS as a monetary policy instrument, can indeed play a role in revitalising Europe’s credit market. However, before using this instrument a number of issues should be addressed: First, the European ABS market has significantly contracted since the crisis. Hence it needs to be revamped through appropriate regulation if securitisation is to play a role in improving the efficiency of resource allocation in the economy. Second, even assuming that this market can expand again, the European ABS market is heterogeneous: lending criteria are different in different countries and banking institutions and the rating methodologies to assess the quality of the borrowers have to take these differences into account. One further element of differentiation is default law, which is specific to national jurisdictions in the euro area. Therefore, the pool of loans will not only be different in terms of the macro risks related to each country of origination (which is a ‘positive’ idiosyncratic risk, because it enables a portfolio manager to differentiate), but also in terms of the normative side, in case of default. The latter introduces uncertainties and inefficiencies in the ABS market that could create arbitrage opportunities. It is also unclear to what extent a direct purchase of these securities by the ECB might have an impact on the credit market. This will depend on, for example, the type of securities targeted in terms of the underlying assets that would be considered as eligible for inclusion (such as loans to small and medium-sized companies, car loans, leases, residential and commercial mortgages). The timing of a possible move by the ECB is also an issue; immediate action would take place in the context of relatively limited market volumes, while if the ECB waits, it might have access to a larger market, provided steps are taken in the next few months to revamp the market. We start by discussing the first of these issues – the size of the EU ABS market. We estimate how much this market could be worth if some specific measures are implemented. We then discuss the different options available to the ECB should they decide to intervene in the EU ABS market. We include a preliminary list of regulatory steps that could be taken to homogenise asset-backed securities in the euro area. We conclude with our recommended course of action.

Defining Europe's Capital Markets Union. Bruegel Policy Contribution Issue 2014/12, 13 November 2014

The new European Commission has signalled that it will work to create a ‘capital markets union’. This is understood as an agenda to expand the non-bank part of Europe’s financial system, which is currently underdeveloped. The aim in the short term is to unlock credit provision as banks are deleveraging, and in the longer term, to favour a more diverse, competitive and resilient financial system. Direct regulation of individual non-bank market segments (such as securitisation, private placements or private equity) might be useful at the margin, but will not per se lead to significant capital markets development or the rebalancing of Europe’s financial system away from the current dominance by banks. To reach these goals, the capital markets union agenda must be broadened to address the framework conditions for the development of individual market segments. Six possible areas for policy initiative are, in increasing order of potential impact and political difficulty: regulation of securities and specific forms of intermediation; prudential regulation, especially of insurance companies and pension funds; regulation of accounting, auditing and financial transparency requirements that apply to companies that seek external finance; a supervisory framework for financial infrastructure firms, such as central counterparties, that supports market integration; partial harmonisation and improvement of insolvency and corporate restructuring frameworks;and partial harmonisation or convergence of tax policies that specifically affect financial investment.

U.S.-Israel Foreign Direct Investment and Terrorism. ACES Working Paper No. 9, 2007

The Israeli economy has been subjected to a continuous flow of terror since its creation. The focus of our study is how terrorism's impacts the level of production of the high-tech sector. The two main objectives and novelties of the paper are: First our paper can be a major contribution to as yet a new subfield in applied microeconomics attempting to measure the impact of terror on economic issues like FDI and Industry output in general and that focused on the High-Tech industries. Second our research is designed to help us understand the impact of terror news, especially on U.S citizens' reactions to terror in Israel. Our terror variable isn't how many bodies or but how many negative articles regarding terror there are in leading American news paper. We focus on the volatility clustering of terror information arrivals in major US financial papers and its impact on high-tech production and FDI to Israel.

The Contribution of the Activation Entropy to the Gas-Phase Stability of Modified Nucleic Acid Duplexes

Tricyclo-DNA (tcDNA) is a sugar-modified analogue of DNA currently tested for the treatment of Duchenne muscular dystrophy in an antisense approach. Tandem mass spectrometry plays a key role in modern medical diagnostics and has become a widespread technique for the structure elucidation and quantification of antisense oligonucleotides. Herein, mechanistic aspects of the fragmentation of tcDNA are discussed, which lay the basis for reliable sequencing and quantification of the antisense oligonucleotide. Excellent selectivity of tcDNA for complementary RNA is demonstrated in direct competition experiments. Moreover, the kinetic stability and fragmentation pattern of matched and mismatched tcDNA heteroduplexes were investigated and compared with non-modified DNA and RNA duplexes. Although the separation of the constituting strands is the entropy-favored fragmentation pathway of all nucleic acid duplexes, it was found to be only a minor pathway of tcDNA duplexes. The modified hybrid duplexes preferentially undergo neutral base loss and backbone cleavage. This difference is due to the low activation entropy for the strand dissociation of modified duplexes that arises from the conformational constraint of the tc-sugar-moiety. The low activation entropy results in a relatively high free activation enthalpy for the dissociation comparable to the free activation enthalpy of the alternative reaction pathway, the release of a nucleobase. The gas-phase behavior of tcDNA duplexes illustrates the impact of the activation entropy on the fragmentation kinetics and suggests that tandem mass spectrometric experiments are not suited to determine the relative stability of different types of nucleic acid duplexes.

Minimal mutation of the cytoplasmic tail inhibits the ability of E-cadherin to activate Rac but not phosphatidylinositol 3-kinase - Direct evidence of a role for cadherin-activated Rac signaling in adhesion and contact formation

Classic cadherins are adhesion-activated cell signaling receptors. In particular, homophilic cadherin ligation can directly activate Rho family GTPases and phosphatidylinositol 3-kinase (PI3-kinase), signaling molecules with the capacity to support the morphogenetic effects of these adhesion molecules during development and disease. However, the molecular basis for cadherin signaling has not been elucidated, nor is its precise contribution to cadherin function yet understood. One attractive hypothesis is that cadherin-activated signaling participates in stabilizing adhesive contacts ( Yap, A. S., and Kovacs, E. M. ( 2003) J. Cell Biol. 160, 11-16). We now report that minimal mutation of the cadherin cytoplasmic tail to uncouple binding of p120-ctn ablated the ability of E-cadherin to activate Rac. This was accompanied by profound defects in the capacity of cells to establish stable adhesive contacts, defects that were rescued by sustained Rac signaling. These data provide direct evidence for a role of cadherin-activated Rac signaling in contact formation and adhesive stabilization. In contrast, cadherin-activated PI3-kinase signaling was not affected by loss of p120-ctn binding. The molecular requirements for E-cadherin to activate Rac signaling thus appear distinct from those that stimulate PI3-kinase, and we postulate that p120-ctn may play a central role in the E-cadherin-Rac signaling pathway.