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.

Complementary Medicine in Nursing Homes - Results of a Mixed Methods Pilot Study

Background ‘Kneipp Therapy’ (KT) is a form of Complementary and Alternative Medicine (CAM) that includes a combination of hydrotherapy, herbal medicine, mind-body medicine, physical activities, and healthy eating. Since 2007, some nursing homes for older adults in Germany began to integrate CAM in the form of KT in care. The study investigated how KT is used in daily routine care and explored the health status of residents and caregivers involved in KT. Methods We performed a cross-sectional pilot study with a mixed methods approach that collected both quantitative and qualitative data in four German nursing homes in 2011. Assessments in the quantitative component included the Quality of Life in Dementia (QUALIDEM), the Short Form 12 Health Survey (SF-12), the Barthel-Index for residents and the Work Ability Index (WAI) and SF-12 for caregivers. The qualitative component addressed the residents’ and caregivers’ subjectively experienced changes after integration of KT. It was conceptualized as an ethnographic rapid appraisal by conducting participant observation and semi-structured interviews in two of the four nursing homes. Results The quantitative component included 64 residents (53 female, 83.2 ± 8.1 years (mean and SD)) and 29 caregivers (all female, 42.0 ± 11.7 years). Residents were multimorbid (8 ± 3 diagnoses), and activities of daily living were restricted (Barthel-Index 60.6 ± 24.4). The caregivers’ results indicated good work ability (WAI 37.4 ± 5.1), health related quality of life was superior to the German sample (SF-12 physical CSS 49.2 ± 8.0; mental CSS 54.1 ± 6.6). Among both caregivers and residents, 89% considered KT to be positive for well-being. The qualitative analysis showed that caregivers perceived emotional and functional benefits from more content and calmer residents, a larger variety in basic care practices, and a more self-determined scope of action. Residents reported gains in attention and caring, and recognition of their lay knowledge. Conclusion Residents showed typical characteristics of nursing home inhabitants. Caregivers demonstrated good work ability. Both reported to have benefits from KT. The results provide a good basis for future projects, e.g. controlled studies to evaluate the effects of CAM in nursing homes.

Hierarchical self-assembly of the DNA-grafted supramolecular polymers

Conjugation of functional entities with a specific set of optical, mechanical or biological properties to DNA strands allows engineering of sophisticated DNA-containing architectures. Among various hybrid systems, DNA-grafted polymers occupy an important place in modern materials science. In this contribution we present the non-covalent synthesis and properties of DNA-grafted linear supramolecular polymers (SPs), which are assembled in a controllable manner from short chimeric DNA-pyrene oligomers. The synthetic oligomers consist of two parts: a 10 nucleotides long DNA chain and a covalently attached segment of variable number of phosphodiester-linked pyrenes. The temperature-dependent formation of DNA-grafted SPs is described by a nucleation-elongation mechanism. The high tendency of pyrenes to aggregate in water, leads to the rapid formation of SPs. The core of the assemblies consists of stacked pyrenes. They form a 1D platform, to which the DNA chains are attached. Combined spectroscopic and microscopic studies reveal that the major driving forces of the polymerization are π-stacking of pyrenes and hydrophobic interactions, and DNA pairing contributes to a lesser extent. AFM and TEM experiments demonstrate that the 1D SPs appear as elongated ribbons with a length of several hundred nanometers. They exhibit an apparent helical structure with a pitch-to-pitch distance of 50±15 nm. Since DNA pairing is a highly selective process, the ongoing studies are aimed to utilize DNA-grafted SPs for the programmable arrangement of functional entities. For example, the addition of non-modified complementary DNA strands to the DNA-grafted SPs leads to the cooperative formation of higher-order assemblies. Also, our experiments suggest that the fluorescent pyrene core of 1D ribbons serves as an efficient donor platform for energy transfer applications.

Hierarchical self-assembly of the DNA-grafted supramolecular polymers

Conjugation of functional entities with a specific set of optical, mechanical or biological properties to DNA strands allows engineering of sophisticated DNA-containing architectures. Among various hybrid systems, DNA-grafted polymers occupy an important place in modern materials science. In this contribution we present the non-covalent synthesis and properties of DNA-grafted linear supramolecular polymers (SPs), which are assembled in a controllable manner from short chimeric DNA-pyrene oligomers. The synthetic oligomers consist of two parts: a 10 nucleotides long DNA chain and a covalently attached segment of variable number of phosphodiester-linked pyrenes. The temperature-dependent formation of DNA-grafted SPs is described by a nucleation-elongation mechanism. The high tendency of pyrenes to aggregate in water, leads to the rapid formation of SPs. The core of the assemblies consists of stacked pyrenes. They form a 1D platform, to which the DNA chains are attached. Combined spectroscopic and microscopic studies reveal that the major driving forces of the polymerization are π-stacking of pyrenes and hydrophobic interactions, and DNA pairing contributes to a lesser extent. AFM and TEM experiments demonstrate that the 1D SPs appear as elongated ribbons with a length of several hundred nanometers. They exhibit an apparent helical structure with a pitch-to-pitch distance of 50±15 nm. Since DNA pairing is a highly selective process, the ongoing studies are aimed to utilize DNA-grafted SPs for the programmable arrangement of functional entities. For example, the addition of non-modified complementary DNA strands to the DNA-grafted SPs leads to the cooperative formation of higher-order assemblies. Also, our experiments suggest that the fluorescent pyrene core of 1D ribbons serves as an efficient donor platform for energy transfer applications.

Usage of Complementary Medicine in Switzerland: Results of the Swiss Health Survey 2012 and Development Since 2007

Background Complementary medicine (CM) is popular in Switzerland. Several CM methods (traditional Chinese medicine/acupuncture, homeopathy, anthroposophic medicine, neural therapy, and herbal medicine) are currently covered by the mandatory basic health insurance when performed by a certified physician. Treatments by non-medical therapists are partially covered by a supplemental and optional health insurance. In this study, we investigated the frequency of CM use including the evolvement over time, the most popular methods, and the user profile. Methods Data of the Swiss Health Surveys 2007 and 2012 were used. In 2007 and 2012, a population of 14,432 and 18,357, respectively, aged 15 years or older answered the written questionnaire. A set of questions queried about the frequency of use of various CM methods within the last 12 months before the survey. Proportions of usage and 95% confidence intervals were calculated for these methods and CM in general. Users and non-users of CM were compared using logistic regression models. Results The most popular methods in 2012 were homeopathy, naturopathy, osteopathy, herbal medicine, and acupuncture. The average number of treatments within the 12 months preceding the survey ranged from 3 for homeopathy to 6 for acupuncture. 25.0% of the population at the age of 15 and older had used at least one CM method in the previous 12 months. People with a chronic illness or a poor self-perceived health status were more likely to use CM. Similar to other countries, women, people of middle age, and those with higher education were more likely to use CM. 59.9% of the adult population had a supplemental health insurance that partly covered CM treatments. Conclusions Usage of CM in Switzerland remained unchanged between 2007 and 2012. The user profile in Switzerland was similar to other countries, such as Germany, United Kingdom, United States or Australia.

The results of a barrier analysis on complementary feeding practices among mothers in the Central River Division of the Gambia

Currently, the barriers to appropriate infant feeding practices are largely unknown in the Central River Division of the Gambia. A questionnaire was developed and implemented by a local Non Governmental Organization (NGO), the Gambia Food and Nutrition Agency, in order to gain more information and ultimately to improve the child mortality rate of the country. There were two participant groups: 88 Doers who are women who had adopted the appropriate complementary feeding practice guidelines as defined by the World Health Organization and 87 Non Doers who are women who had in some way strayed from the appropriate complementary feeding practice guidelines. The questionnaire included aspects of the Health Belief Model which can be used in the development of a future intervention. The Yes/No questions were analyzed using the Chi-square statistical method and the open-ended questions used a descriptive analysis method of evaluation. The constructs for perceived susceptibility, perceived action efficacy, perceived self efficacy, cues for action and perception of divine showed significant differences between the Doers and the Non Doers (p<0.05). The descriptive analysis revealed that both participant groups had a limited understanding of the preventative qualities of the adoption of appropriate complementary feeding practices. The women in both of groups also showed a strong perception of divine will. Women in the Central River Division perceive their husband and in-laws to be the most influential in the decision-making process regarding infant feeding practices. Recommendations for future interventions must acknowledge the importance and influence of the community surrounding the women in their adoption of the appropriate infant feeding practices. It would also be important to educate women about of the specific guidelines of the appropriate complementary feeding practices, specifically the delay in early initiation of complementary feeding. The results of this barrier analysis provide useful information to plan and implement an effective intervention to improve the child mortality rate in the Gambia. ^

Are trading partners complementary in international trade?

We use a unique dataset on trading transactions at the firm level to investigate a complementary effect in international transactions between sellers and buyers; trading transactions are more likely to be international when both sellers and buyers are large in size than when either sellers or buyers are large. Our econometric analysis provides evidence for the complementary effect between trading partners on the likelihood of international trade, which is most prominent for exports from North to South.

Self-organizing cultured neural networks: Image analysis techniques for longitudinal tracking and modeling of the underlying network structure

Esta tesis estudia la evolución estructural de conjuntos de neuronas como la capacidad de auto-organización desde conjuntos de neuronas separadas hasta que forman una red (clusterizada) compleja. Esta tesis contribuye con el diseño e implementación de un algoritmo no supervisado de segmentación basado en grafos con un coste computacional muy bajo. Este algoritmo proporciona de forma automática la estructura completa de la red a partir de imágenes de cultivos neuronales tomadas con microscopios de fase con una resolución muy alta. La estructura de la red es representada mediante un objeto matemático (matriz) cuyos nodos representan a las neuronas o grupos de neuronas y los enlaces son las conexiones reconstruidas entre ellos. Este algoritmo extrae también otras medidas morfológicas importantes que caracterizan a las neuronas y a las neuritas. A diferencia de otros algoritmos hasta el momento, que necesitan de fluorescencia y técnicas inmunocitoquímicas, el algoritmo propuesto permite el estudio longitudinal de forma no invasiva posibilitando el estudio durante la formación de un cultivo. Además, esta tesis, estudia de forma sistemática un grupo de variables topológicas que garantizan la posibilidad de cuantificar e investigar la progresión de las características principales durante el proceso de auto-organización del cultivo. Nuestros resultados muestran la existencia de un estado concreto correspondiente a redes con configuracin small-world y la emergencia de propiedades a micro- y meso-escala de la estructura de la red. Finalmente, identificamos los procesos físicos principales que guían las transformaciones morfológicas de los cultivos y proponemos un modelo de crecimiento de red que reproduce el comportamiento cuantitativamente de las observaciones experimentales. ABSTRACT The thesis analyzes the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. In particular, it contributes with the design and implementation of a graph-based unsupervised segmentation algorithm, having an associated very low computational cost. The processing automatically retrieves the whole network structure from large scale phase-contrast images taken at high resolution throughout the entire life of a cultured neuronal network. The network structure is represented by a mathematical object (a matrix) in which nodes are identified neurons or neurons clusters, and links are the reconstructed connections between them. The algorithm is also able to extract any other relevant morphological information characterizing neurons and neurites. More importantly, and at variance with other segmentation methods that require fluorescence imaging from immunocyto- chemistry techniques, our measures are non invasive and entitle us to carry out a fully longitudinal analysis during the maturation of a single culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main networks characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graphs micro- and meso-scale properties emerge. Finally, we identify the main physical processes taking place during the cultures morphological transformations, and embed them into a simplified growth model that quantitatively reproduces the overall set of experimental observations.

Self-organizing cultured neural networks: Image analysis techniques for longitudinal tracking and modeling of the underlying network structure (versión actualizada)

Esta tesis estudia la evolución estructural de conjuntos de neuronas como la capacidad de auto-organización desde conjuntos de neuronas separadas hasta que forman una red (clusterizada) compleja. Esta tesis contribuye con el diseño e implementación de un algoritmo no supervisado de segmentación basado en grafos con un coste computacional muy bajo. Este algoritmo proporciona de forma automática la estructura completa de la red a partir de imágenes de cultivos neuronales tomadas con microscopios de fase con una resolución muy alta. La estructura de la red es representada mediante un objeto matemático (matriz) cuyos nodos representan a las neuronas o grupos de neuronas y los enlaces son las conexiones reconstruidas entre ellos. Este algoritmo extrae también otras medidas morfológicas importantes que caracterizan a las neuronas y a las neuritas. A diferencia de otros algoritmos hasta el momento, que necesitan de fluorescencia y técnicas inmunocitoquímicas, el algoritmo propuesto permite el estudio longitudinal de forma no invasiva posibilitando el estudio durante la formación de un cultivo. Además, esta tesis, estudia de forma sistemática un grupo de variables topológicas que garantizan la posibilidad de cuantificar e investigar la progresión de las características principales durante el proceso de auto-organización del cultivo. Nuestros resultados muestran la existencia de un estado concreto correspondiente a redes con configuracin small-world y la emergencia de propiedades a micro- y meso-escala de la estructura de la red. Finalmente, identificamos los procesos físicos principales que guían las transformaciones morfológicas de los cultivos y proponemos un modelo de crecimiento de red que reproduce el comportamiento cuantitativamente de las observaciones experimentales. ABSTRACT The thesis analyzes the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. In particular, it contributes with the design and implementation of a graph-based unsupervised segmentation algorithm, having an associated very low computational cost. The processing automatically retrieves the whole network structure from large scale phase-contrast images taken at high resolution throughout the entire life of a cultured neuronal network. The network structure is represented by a mathematical object (a matrix) in which nodes are identified neurons or neurons clusters, and links are the reconstructed connections between them. The algorithm is also able to extract any other relevant morphological information characterizing neurons and neurites. More importantly, and at variance with other segmentation methods that require fluorescence imaging from immunocyto- chemistry techniques, our measures are non invasive and entitle us to carry out a fully longitudinal analysis during the maturation of a single culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main networks characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graphs micro- and meso-scale properties emerge. Finally, we identify the main physical processes taking place during the cultures morphological transformations, and embed them into a simplified growth model that quantitatively reproduces the overall set of experimental observations.

Controlling cell attachment on contoured surfaces with self-assembled monolayers of alkanethiolates on gold.

This paper describes a method based on experimentally simple techniques--microcontact printing and micromolding in capillaries--to prepare tissue culture substrates in which both the topology and molecular structure of the interface can be controlled. The method combines optically transparent contoured surfaces with self-assembled monolayers (SAMs) of alkanethiolates on gold to control interfacial characteristics; these tailored interfaces, in turn, control the adsorption of proteins and the attachment of cells. The technique uses replica molding in poly(dimethylsiloxane) molds having micrometer-scale relief patterns on their surfaces to form a contoured film of polyurethane supported on a glass slide. Evaporation of a thin (< 12 nm) film of gold on this surface-contoured polyurethane provides an optically transparent substrate, on which SAMs of terminally functionalized alkanethiolates can be formed. In one procedure, a flat poly(dimethylsiloxane) stamp was used to form a SAM of hexadecanethiolate on the raised plateaus of the contoured surface by contact printing hexadecanethiol [HS(CH2)15CH3]; a SAM terminated in tri(ethylene glycol) groups was subsequently formed on the bare gold remaining in the grooves by immersing the substrate in a solution of a second alkanethiol [HS(CH2)11(OCH2CH2)3OH]. Then this patterned substrate was immersed in a solution of fibronectin, the protein adsorbed only on the methyl-terminated plateau regions of the substrate [the tri(ethylene glycol)-terminated regions resisted the adsorption of protein]; bovine capillary endothelial cells attached only on the regions that adsorbed fibronectin. A complementary procedure confined protein adsorption and cell attachment to the grooves in this substrate.

Herbs or natural substances as complementary therapies for chronic kidney disease: ideas for future studies

Chronic kidney disease (CKD) is an increasingly common condition with limited treatment options that is placing a major financial and emotional burden on the community. The use of complementary and alternative medicines (CAMS) has increased many-fold over the past decade. Although several compelling studies show renal toxicities and an adverse outcome from use of some CAMS, there is also emerging evidence in the literature that some may be renoprotective. Many nephrologists are unaware of these potential therapeutic benefits in treating CKD, or they are reluctant to consider them in research trials for fear of adverse effects (including nephrotoxicity) or deleterious interaction with co-prescribed, conventional medicines. The increased use of self-prescribed CAMS by their patients suggests that practitioners and researchers should keep abreast of the current information on these agents. A primary goal of this article was to review the available scientific evidence for the use of herbs or natural substances as a complementary treatment for patients with CKD. A further goal was to report the literature on herbs that have been reported to cause kidney failure.

String Measure Applied to String Self-Organizing Maps and Networks of Evolutionary Processors

* Supported by projects CCG08-UAM TIC-4425-2009 and TEC2007-68065-C03-02

Unlinked Embedded Graphs

This paper is a self-contained development of an invariant of graphs embedded in three-dimensional Euclidean space using the Jones polynomial and skein theory. Some examples of the invariant are computed. An unlinked embedded graph is one that contains only trivial knots or links. Examples show that the invariant is sufficiently powerful to distinguish some different unlinked embeddings of the same graph.

Carpal tunnel syndrome and computer exposure at work in two large complementary cohorts.

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Desymmetrization of an octahedral coordination complex Inside a self-assembled exoskeleton

The synthesis of a centrally functionalized, ribbon-shaped [6]polynorbornane ligand L that self-assembles with PdII cations into a (Pd2L4) coordination cage is reported. The shape-persistent (Pd2L4) cage contains two axial cationic centers and an array of four equatorial H-bond donors pointing directly towards the center of the cavity. This precisely defined supramolecular environment is complementary to the geometry of classic octahedral complexes [M(XY)6] with six diatomic ligands. Very strong binding of [Pt(CN)6]2- to the cage was observed, with the structure of the host-guest complex ([Pt(CN)6]@Pd2L4) supported by NMR spectroscopy, MS, and X-ray data. The self-assembled shell imprints its geometry on the encapsulated guest, and desymmetrization of the octahedral platinum species by the influence of the D4h-symmetric second coordination sphere was evidenced by IR spectroscopy. [Fe(CN)6]3- and square-planar [Pt(CN)4]2- were strongly bound. Smaller octahedral anions such as [SiF6]2-, neutral carbonyl complexes ([M(CO)6]; M=Cr, Mo, W) and the linear [Ag(CN)2]- anion were only weakly bound, showing that both size and charge match are key factors for high-affinity binding.