Canonical proof nets for classical logic

Proof nets provide abstract counterparts to sequent proofs modulo rule permutations; the idea being that if two proofs have the same underlying proof-net, they are in essence the same proof. Providing a convincing proof-net counterpart to proofs in the classical sequent calculus is thus an important step in understanding classical sequent calculus proofs. By convincing, we mean that (a) there should be a canonical function from sequent proofs to proof nets, (b) it should be possible to check the correctness of a net in polynomial time, (c) every correct net should be obtainable from a sequent calculus proof, and (d) there should be a cut-elimination procedure which preserves correctness. Previous attempts to give proof-net-like objects for propositional classical logic have failed at least one of the above conditions. In Richard McKinley (2010) [22], the author presented a calculus of proof nets (expansion nets) satisfying (a) and (b); the paper defined a sequent calculus corresponding to expansion nets but gave no explicit demonstration of (c). That sequent calculus, called LK∗ in this paper, is a novel one-sided sequent calculus with both additively and multiplicatively formulated disjunction rules. In this paper (a self-contained extended version of Richard McKinley (2010) [22]), we give a full proof of (c) for expansion nets with respect to LK∗, and in addition give a cut-elimination procedure internal to expansion nets – this makes expansion nets the first notion of proof-net for classical logic satisfying all four criteria.

Efficacy of quality criteria to identify potentially harmful information: a cross-sectional survey of complementary and alternative medicine web sites.

BACKGROUND: Many users search the Internet for answers to health questions. Complementary and alternative medicine (CAM) is a particularly common search topic. Because many CAM therapies do not require a clinician's prescription, false or misleading CAM information may be more dangerous than information about traditional therapies. Many quality criteria have been suggested to filter out potentially harmful online health information. However, assessing the accuracy of CAM information is uniquely challenging since CAM is generally not supported by conventional literature. OBJECTIVE: The purpose of this study is to determine whether domain-independent technical quality criteria can identify potentially harmful online CAM content. METHODS: We analyzed 150 Web sites retrieved from a search for the three most popular herbs: ginseng, ginkgo and St. John's wort and their purported uses on the ten most commonly used search engines. The presence of technical quality criteria as well as potentially harmful statements (commissions) and vital information that should have been mentioned (omissions) was recorded. RESULTS: Thirty-eight sites (25%) contained statements that could lead to direct physical harm if acted upon. One hundred forty five sites (97%) had omitted information. We found no relationship between technical quality criteria and potentially harmful information. CONCLUSIONS: Current technical quality criteria do not identify potentially harmful CAM information online. Consumers should be warned to use other means of validation or to trust only known sites. Quality criteria that consider the uniqueness of CAM must be developed and validated.

Evaluating the prevalence, content and readability of complementary and alternative medicine (CAM) web pages on the internet.

Complementary and alternative medicine (CAM) use is growing rapidly. As CAM is relatively unregulated, it is important to evaluate the type and availability of CAM information. The goal of this study is to deter-mine the prevalence, content and readability of online CAM information based on searches for arthritis, diabetes and fibromyalgia using four common search engines. Fifty-eight of 599 web pages retrieved by a "condition search" (9.6%) were CAM-oriented. Of 216 CAM pages found by the "condition" and "condition + herbs" searches, 78% were authored by commercial organizations, whose pur-pose involved commerce 69% of the time and 52.3% had no references. Although 98% of the CAM information was intended for consumers, the mean read-ability was at grade level 11. We conclude that consumers searching the web for health information are likely to encounter consumer-oriented CAM advertising, which is difficult to read and is not supported by the conventional literature.

The recombinant adeno-associated virus vector (rAAV2)-mediated apolipoprotein B mRNA-specific hammerhead ribozyme: a self-complementary AAV2 vector improves the gene expression.

BACKGROUND: In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. To reduce the levels of apoB mRNA, we have designed an apoB mRNA-specific hammerhead ribozyme targeted at nucleotide sequences GUA6679 (RB15) mediated by adenovirus, which efficiently cleaves and decreases apoB mRNA by 80% in mouse liver and attenuates the hyperlipidemic condition. In the current study, we used an adeno-associated virus vector, serotype 2 (AAV2) and a self-complementary AAV2 vector (scAAV2) to demonstrate the effect of long-term tissue-specific gene expression of RB15 on the regulation apoB mRNA in vivo. METHODS: We constructed a hammerhead ribozyme RB15 driven by a liver-specific transthyretin (TTR) promoter using an AAV2 vector (rAAV2-TTR-RB15). HepG2 cells and hyperlipidemic mice deficient in both the low density lipoprotein receptor and the apoB mRNA editing enzyme genes (LDLR-/-Apobec1-/-; LDb) were transduced with rAAV2-TTR-RB15 and a control vector rAAV-TTR-RB15-mutant (inactive ribozyme). The effects of ribozyme RB15 on apoB metabolism and atherosclerosis development were determined in LDb mice at 5-month after transduction. A self-complementary AAV2 vector expressing ribozyme RB15 (scAAV2-TTR-RB15) was also engineered and used to transduce HepG2 cells. Studies were designed to compare the gene expression efficiency between rAAV2-TTR-RB15 and scAAV2-TTR-RB15. RESULTS: The effect of ribozyme RB15 RNA on reducing apoB mRNA levels in HepG2 cells was observed only on day-7 after rAAV2-TTR-RB15 transduction. And, at 5-month after rAAV2-TTR-RB15 treatment, the apoB mRNA levels in LDb mice were significantly decreased by 43%, compared to LDb mice treated with control vector rAAV2-TTR-RB15-mutant. Moreover, both the rAAV2-TTR-RB15 viral DNA and ribozyme RB15 RNA were still detectable in mice livers at 5-month after treatment. However, this rAAV2-TTR-RB15 vector mediated a prolonged but low level of ribozyme RB15 gene expression in the mice livers, which did not produce the therapeutic effects on alteration the lipid levels or the inhibition of atherosclerosis development. In contrast, the ribozyme RB15 RNA mediated by scAAV2-TTR-RB15 vector was expressed immediately at day-1 after transduction in HepG2 cells. The apoB mRNA levels were decreased 47% (p = 0.001), compared to the control vector scAAV2-TTR-RB15-mutant. CONCLUSION: This study provided evidence that the rAAV2 single-strand vector mediated a prolonged but not efficient transduction in mouse liver. However, the scAAV2 double-strand vector mediated a rapid and efficient gene expression in liver cells. This strategy using scAAV2 vectors represents a better approach to express small molecules such as ribozyme.

Twenty-three per cent of the Swiss adult population are using complementary medicine

Aim of the study: This study investigated the use among the Swiss adult population and the regional dissemination in Switzerland of various methods of complementary medicine (CM). It focused on CM methods that required visiting a physician or therapist and excluded e.g. over-the-counter drugs. Data and Methods: Data of the Swiss Health Survey 2007 were obtained from the Swiss Federal Statistical Office. This survey is performed every 5 years in a sample and is representative of the Swiss resident population from the age of 15 on. It consists of a telephone interview followed by a written questionnaire (2007: 18'760 and 14'432 respondents, respectively) and includes questions about people's state of health, general living conditions, lifestyle, health insurance and usage of health services. Users and non-users of CM were compared using logistic regression models. Results: 23.0 % of the Swiss adult population (women: 30.5 %, men: 15.2 %) used CM during the 12 months before the survey. Homeopathy (6.4 %), osteopathy (5.4 %) and acupuncture (4.9 %) were the most popular methods. The average number of treatments within 12 months for these three methods was 3.1 ± 3.6, 3.5 ± 3.3 and 6.6 ± 5.8, respectively. For treatments with homeopathy and acupuncture, medical practitioners were more commonly consulted than non-medical practitioners, for treatments with osteopathy no difference was found. By means of logistic regression, CM users and non-users were compared. There were significant differences in the use of CM between genders, age groups, levels of education and areas of living. Women, people aged 25 to 64 years, and people with higher levels of education used CM more commonly than men, people below 25 or above 64 years of age, or those with poorer education. Lake Geneva region and central Switzerland had a higher proportion of CM users than the other regions. Discussion: Almost one fourth of the Swiss adult population had used CM within 12 months before the survey. User profiles were comparable to those in other countries. Despite a generally lower self-perceived health status, elderly people were less likely to use CM. Reference: Klein SD, Frei-Erb M, Wolf U. Usage of complementary medicine across Switzerland. Results of the Swiss Health Survey 2007. Swiss Med Wkly. 2012;142:w13666.

Twenty-three per cent of the Swiss adult population are using complementary medicine

Aim of the study Various forms of complementary medicine (CM) play an important role in the Swiss health care system, they are appreciated by a majority of the population and mostly used complementarily rather than alternatively to conventional medicine. This study investigates, how many people in Switzerland are actually being treated with CM, and what the most popular methods of CM are. Data Data of the Swiss Health Survey 2007 were obtained from the Swiss Federal Statistical Office. This survey is performed every 5 years amongst a sample of the Swiss resident population above 15 years of age. It consists of a telephone interview followed by a written questionnaire (2007: 18'760 and 14'432 respondents, respectively) and includes questions about people's state of health, general living conditions, lifestyle, health insurance and usage of health services. Results 23.0% of the Swiss adult population (women: 30.5%, men: 15.2%) used CM during the 12 months before the survey. Homeopathy (6.4%), osteopathy (5.4%) and acupuncture (4.9%) were the most popular methods. The average number of treatments within 12 months for these three methods was 3.1, 3.5 and 6.6, respectively. For treatments with homeopathy and acupuncture, medical practitioners were more commonly consulted than non-medical practitioners, for treatments with osteopathy no difference was found. By means of logistic regression, CM users and non-users were compared. There were significant differences in the use of CM between genders, age groups, levels of education and areas of living. Women, people aged 25 to 64 years, and people with higher education used CM more commonly than men, people below 25 or above 64 years of age, or those with poorer education. Lake Geneva region and central Switzerland had a higher proportion of CM users than the other regions. Discussion While 2 years ago, 67.0% of the Swiss population approved a referendum in favour of CM, we find that 23.0% are in fact using it. Current political discussions focus on effectiveness, cost effectiveness and suitability of CM to decide which methods should be permanently covered by the basic health insurance.

Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA

The fluorinated olefinic peptide nucleic acid (F-OPA) system was designed as a peptide nucleic acid (PNA) analogue in which the base carrying amide moiety was replaced by an isostructural and isoelectrostatic fluorinated C-C double bond, locking the nucleobases in one of the two possible rotameric forms. By comparison of the base-pairing properties of this analogue with its nonfluorinated analogue OPA and PNA, we aimed at a closer understanding of the role of this amide function in complementary DNA recognition. Here we present the synthesis of the F-OPA monomer building blocks containing the nucleobases A, T, and G according to the MMTr/Acyl protecting group scheme. Key steps are a selective desymmetrization of the double bond in the monomer precursor via lactonization as well as a highly regioselective Mitsunobu reaction for the introduction of the bases. PNA decamers containing single F-OPA mutations and fully modified F-OPA decamers and pentadecamers containing the bases A and T were synthesized by solid-phase peptide chemistry, and their hybridization properties with complementary parallel and antiparallel DNA were assessed by UV melting curves and CD spectroscopic methods. The stability of the duplexes formed by the decamers containing single (Z)-F-OPA modifications with parallel and antiparallel DNA was found to be strongly dependent on their position in the sequence with T(m) values ranging from +2.4 to -8.1 degrees C/modification as compared to PNA. Fully modified F-OPA decamers and pentadecamers were found to form parallel duplexes with complementary DNA with reduced stability compared to PNA or OPA. An asymmetric F-OPA pentadecamer was found to form a stable self-complex (T(m) approximately 65 degrees C) of unknown structure. The generally reduced affinity to DNA may therefore be due to an increased propensity for self-aggregation

A Research Roadmap for Complementary and Alternative Medicine – What We Need to Know by 2020

Background: The CAMbrella coordination action was funded within the Framework Programme 7. Its aim is to provide a research roadmap for clinical and epidemiological research for complementary and alternative medicine (CAM) that is appropriate for the health needs of European citizens and acceptable to their national research institutes and healthcare providers in both public and private sectors. One major issue in the European research agenda is the demographic change and its impact on health care. Our vision for 2020 is that there is an evidence base that enables European citizens to make informed decisions about CAM, both positive and negative. This roadmap proposes a strategic research agenda for the field of CAM designed to address future European health care challenges. This roadmap is based on the results of CAMbrella’s several work packages, literature reviews and expert discussions including a consensus meeting. Methods: We first conducted a systematic literature review on key issues in clinical and epidemiological research in CAM to identify the general concepts, methods and the strengths and weaknesses of current CAM research. These findings were discussed in a workshop (Castellaro, Italy, September 7–9th 2011) with international CAM experts and strategic and methodological recommendations were defined in order to improve the rigor and relevance of CAM research. These recommendations provide the basis for the research roadmap, which was subsequently discussed in a consensus conference (Järna, Sweden, May 9–11th 2012) with all CAMbrella members and the CAMbrella advisory board. The roadmap was revised after this discussion in CAMbrella Work Package (WP) 7 and finally approved by CAMbrella’s scientific steering committee on September 26th 2012. Results: Our main findings show that CAM is very heterogenous in terms of definitions and legal regulations between the European countries. In addition, citizens’ needs and attitudes towards CAM as well as the use and provision of CAM differ significantly between countries. In terms of research methodology, there was consensus that CAM researchers should make use of all the commonly accepted scientific research methods and employ those with utmost diligence combined in a mixed methods framework. Conclusions: We propose 6 core areas of research that should be investigated to achieve a robust knowledge base and to allow stakeholders to make informed decisions. These are: Research into the prevalence of CAM in Europe: Reviews show that we do not know enough about the circumstances in which CAM is used by Europeans. To enable a common European strategic approach, a clear picture of current use is of the utmost importance. Research into differences regarding citizens’ attitudes and needs towards CAM: Citizens are the driver for CAM utilization. Their needs and views on CAM are a key priority, and their interests must be investigated and addressed in future CAM research. Research into safety of CAM: Safety is a key issue for European citizens. CAM is considered safe, but reliable data is scarce although urgently needed in order to assess the risk and cost-benefit ratio of CAM. Research into the comparative effectiveness of CAM: Everybody needs to know in what situation CAM is a reasonable choice. Therefore, we recommend a clear emphasis on concurrent evaluation of the overall effectiveness of CAM as an additional or alternative treatment strategy in real-world settings. Research into effects of context and meaning: The impact of effects of context and meaning on the outcome of CAM treatments must be investigated; it is likely that they are significant. Research into different models of CAM health care integration: There are different models of CAM being integrated into conventional medicine throughout Europe, each with their respective strengths and limitations. These models should be described and concurrently evaluated; innovative models of CAM provision in health care systems should be one focus for CAM research. We also propose a methodological framework for CAM research. We consider that a framework of mixed methodological approaches is likely to yield the most useful information. In this model, all available research strategies including comparative effectiveness research utilising quantitative and qualitative methods should be considered to enable us to secure the greatest density of knowledge possible. Stakeholders, such as citizens, patients and providers, should be involved in every stage of developing the specific and relevant research questions, study design and the assurance of real-world relevance for the research. Furthermore, structural and sufficient financial support for research into CAM is needed to strengthen CAM research capacity if we wish to understand why it remains so popular within the EU. In order to consider employing CAM as part of the solution to the health care, health creation and self-care challenges we face by 2020, it is vital to obtain a robust picture of CAM use and reliable information about its cost, safety and effectiveness in real-world settings. We need to consider the availability, accessibility and affordability of CAM. We need to engage in research excellence and utilise comparative effectiveness approaches and mixed methods to obtain this data. Our recommendations are both strategic and methodological. They are presented for the consideration of researchers and funders while being designed to answer the important and implicit questions posed by EU citizens currently using CAM in apparently increasing numbers. We propose that the EU actively supports an EUwide strategic approach that facilitates the development of CAM research. This could be achieved in the first instance through funding a European CAM coordinating research office dedicated to foster systematic communication between EU governments, public, charitable and industry funders as well as researchers, citizens and other stakeholders. The aim of this office would be to coordinate research strategy developments and research funding opportunities, as well as to document and disseminate international research activities in this field. With the aim to develop sustainability as second step, a European Centre for CAM should be established that takes over the monitoring and further development of a coordinated research strategy for CAM, as well as it should have funds that can be awarded to foster high quality and robust independent research with a focus on citizens health needs and pan-European collaboration. We wish to establish a solid funding for CAM research to adequately inform health care and health creation decision-making throughout the EU. This centre would ensure that our vision of a common, strategic and scientifically rigorous approach to CAM research becomes our legacy and Europe’s reality. We are confident that our recommendations will serve these essential goals for EU citizens.

High prevalence but limited evidence in complementary and alternative medicine: guidelines for future research

The use of complementary and alternative Medicine (CAM) has increased over the past two decades in Europe. Nonetheless, research investigating the evidence to support its use remains limited. The CAMbrella project funded by the European Commission aimed to develop a strategic research agenda starting by systematically evaluating the state of CAM in the EU. CAMbrella involved 9 work packages covering issues such as the definition of CAM; its legal status, provision and use in the EU; and a synthesis of international research perspectives. Based on the work package reports, we developed a strategic and methodologically robust research roadmap based on expert workshops, a systematic Delphi-based process and a final consensus conference. The CAMbrella project suggests six core areas for research to examine the potential contribution of CAM to the health care challenges faced by the EU. These areas include evaluating the prevalence of CAM use in Europe; the EU cititzens’ needs and attitudes regarding CAM; the safety of CAM; the comparative effectiveness of CAM; the effects of meaning and context on CAM outcomes; and different models for integrating CAM into existing health care systems. CAM research should use methods generally accepted in the evaluation of health services, including comparative effectiveness studies and mixed-methods designs. A research strategy is urgently needed, ideally led by a European CAM coordinating research office dedicated to fostering systematic communication between EU governments, the public, charitable and industry funders, researchers and other stakeholders. A European Centre for CAM should also be established to monitor and further a coordinated research strategy with sufficient funds to commission and promote high quality, independent research focusing on the public’s health needs and pan-European collaboration. There is a disparity between highly prevalent use of CAM in Europe and solid knowledge about it. A strategic approach on CAM research should be established to investigate the identified gaps of knowledge and to address upcoming health care challenges.