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[ "Acknowledgments ", "All participants, both patients and normal controls, are acknowledged for giving valuable data for the study. The authors also thank the Psychiatry Department at Hospital Kuala Lumpur for allowing data collection from the patients. The Department of Psychology at International Islamic University Malaysia is acknowledged for supporting Eka Juliana. ", "Author details ", "1Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia. 2Department of Psychology, International Islamic University Malaysia, Jalan Gombak, Kuala Lumpur, Selangor, Malaysia. 3Department of Psychology & Counseling, Sultan Idris Education University, Tanjong Malim, Perak, Malaysia. 4School of Psychology & Speech Pathology, Curtin University, Perth, Western Australia 6845, Australia. ", "J Abnorm Psychol 1986, 95:144–149. Dalgleish T, Williams JMG, Golden AJ, Perkins N, Barrett LF, Barnard PJ, Yeung AC, Murphy V, Elward R, Tchanturia K, Watkins E: Reduced specificity of autobiographical memory and depression: The role of executive control. J Exp Psychol Gen 2007, 136:23–42. Decker AD, Hermans D, Raes F, Eelen P: Autobiographical memory specificity and trauma in inpatient adolescents. J Clin Child Adolesc Psychol 2003, 32:22–31. 4. Mackinger HF, Pachinger MM, Leibetseder MM, Fartacek RR: Autobiographical memories in women remitted from major depression. J Abnorm Psychol 2000, 109:331–334. 5. Williams JMG, Scott J: Autobiographical memory in depression. Psychol Med 1988, 18:69–695. Brittlebank AD, Scott J, Williams JMG, Ferrier IN: Autobiographical memory in depression: State or trait marker? Br J Psychiatry 1993, 162:118–121. Peeters F, Wessel I, Merckelbach H, Boon-Vermeeren M: Autobiographical memory specificity and the course of major depressive disorder. Compr Psychiatry 2002, 43:344–350. Kaviani H, Rahimi P, Naghavi HM: Iranian depressed patients attempting suicide showed impaired memory and problem-solving. Arch Iran Med 2004, 7:1113–1117. Leibetseder MM, Rohrer RR, Mackinger HF, Fartacek RR: Suicide attempts: Patients with and without an affective disorder show impaired autobiographical memory specificity. Cogn Emotion 2006, 3/4:516–526. 10. Rekart KN, Mineka S, Zinbarg RE: Autobiographic memory in dysphoric and non-dysphoric college students using a computerised version of the AMT. Cogn Emotion 2006, 3/4:506–515. 11. Drummond LE, Dritschel B, Astell A, O’Carroll RE, Dalgleish T: Effects of age, dysphoria, and emotion-focusing on autobiographical memory specificity in children. Cogn Emotion 2006, 3/4:488–505. Kleim B, Ehlers A: Reduced autobiographical memory specificity predicts depression and posttraumatic stress disorder after recent trauma. J Consult Clin Psychol 2008, 76:231–242. Sumner JA, Griffith JW, Mineka S, Rekart KN, Zinbarg RE, Craske MG: Overgeneral autobiographical memory and chronic interpersonal stress as predictors of the course of depression in adolescents. Cogn Emotion 2011, 25:183–192. 14. Hermans D, Vandromme H, Debeer E, Raes F, Demyttenaere K, Brunfaut E, Williams JM: Overgeneral autobiographical memory predicts diagnostic status in depression. Behav Res Ther 2008, 46:668–677. Sumner JA, Griffith JW, Mineka S: Overgeneral autobiographical memory as a predictor of the course of depression: A meta-analysis. Behav Res Ther 2010, 48:614–625. 16. Goddard L, Dritschel B, Burton A: Role of autobiographical memory in social problem solving and depression. J Abnorm Psychol 1996, 105:609–616. Evans J, Williams JMG, O’Loughlin S, Howells K: Autobiographical memory and problem-solving strategies of parasuicide patients. Psychol Med 1992, 22:399–405. 18. Conway MA, Pleydell-Pearce CW: The construction of autobiographical ", "31. knowledge. In Remembering our past: Studies in autobiographical memory. Edited by Rubin DC. Cambridge, UK: Cambridge University Press; 1996:67–93. 20. Williams DM, Hollan JD: The process of retrieval from very long-term memory. Cogn Sci 1981, 5:87–119. 21. Moscovitch M: Recovered consciousness: A hypothesis concerning modularity and episodic memory. J Clin Exp Neuropsychol 1995, 17:276–290. Tulving E: Elements of episodic memory. Oxford, UK: Clarendon Press; 1983. 22. 23. Williams JMG, Barnhofer T, Crane C, Hermans D, Raes F, Watkins E, Dalgleish 24. T: Autobiographical memory specificity and emotional disorder. Psychol Bull 2007, 133:122–148. Sumner JA: The mechanism underlying overgeneral autobiographical memory: An evaluative review of evidence for the CaR-FA-X model. Clin Psychol Rev 2012, 32:34–48. 25. Hermans D, Defranc A, Raes F, Williams JMG, Eelen P: Reduced autobiographical memory specificity as an avoidant coping style. Br J Clin Psychol 2005, 44:583–589. 26. Raes F, Herman D, Williams JMG, Eelen P: Reduced autobiographical memory specificity and affect regulation. Cogn Emotion 2006, 3/4:402–429. 27. Barnard PJ, Watkins ER, Ramponi C: Reducing specificity of autobiographical memory in nonclinical participants: The role of rumination and schematic models. Cogn Emotion 2006, 3/4:328–350. 28. Williams JMG, Ellis NC, Tyers C, Healy H, Rose G, MacLeod AK: The specificity 29. of autobiographical memory and imageability of the future. Mem Cogn 1996, 24:116–125. Spinhoven P, Bockting CLH, Kremers IP, Schene AH, Williams JMG: The endorsement of dysfunctional attitudes is associated with an impaired retrieval of specific autobiographical memories in response to matching cues. Memory 2007, 15:324–338. 30. Moulds ML, Kandris E, Williams AD: The impact of rumination on memory for self-referent material. Memory 2007, 15:814–821. Sutherland K, Bryant RA: Rumination and overgeneral autobiographical memory. Behav Res Ther 2007, 45:2407–2416. 32. Williams JMG, Chan S, Crane C, Barnhofer T, Eade J, Healy H: Retrieval of autobiographical memories: The mechanisms and consequences of truncated search. Cogn Emotion 2006, 3/4:351–382. 33. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders DSM-5. 5th edition. Washington, DC: American Psychiatric Publishing; 2013. 34. Galton F: Inquiries into human faculty and its development. London: Macmillan; 1883. 35. Haque S, Conway MA: Sampling the process of autobiographical memory construction. Eur J Cogn Psychol 2001, 13:529–547. 36. Beck AT, Steer RA: Beck Depression Inventory: Manual. Orlando, FL: Harcourt Brace; 1993. 37. Haque S, Conway MA: Direct and generative retrieval of autobiographical memories. Bangladesh J Psychol 2000, 18:51–74. 38. DeWinter JCF: Using the Student’s t-test with extremely small sample sizes. 39. 40. Pract Assess Res Eval 2013, 18:1–12. Satterthwaite FE: An approximate distribution of estimates of variance components. Biom Bull 1946, 2:110–114. Kuyken W, Brewin CR: Autobiographical memory functioning in depression and reports of early abuse. J Abnorm Psychol 1995, 104:585–591. 41. Ready RE, Weinberger MI, Jones KM: How happy have you felt lately? Two diary studies of emotion recall in older and younger adults. Cogn Emotion 2007, 21:728–757. ", "Cite this article as: Haque et al.: Autobiographical memory and hierarchical search strategies in depressed and non-depressed participants. BMC Psychiatry 2014 14:310. " ]

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[ "Chronic inflammatory systemic diseases An evolutionary trade-off between acutely beneficial but chronically harmful programs ", "Rainer H. Straub1,* and Carsten Schradin2,3,4 ", "1Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Division of Rheumatology, Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany; 2Universite´ De Strasbourg, IPHC-DEPE, 23 Rue Becquerel, Strasbourg 67087, France; 3CNRS (Centre National De La Recherche Scientifique), UMR7178, Strasbourg 67087, France; 4School of Animal, Plant and Environmental Sciences, University of the Witwatersrand, Johannesburg, South Africa ", "*Corresponding author. Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Division of Rheumatology, Department of Internal Medicine, University Hospital 93042 Regensburg, Germany. Tel: +49 941 944 7120; E-mail: rainer.straub@ukr.de ", "Received 29 June 2015; revised version accepted 23 December 2015 ", "A B S T R A C T ", "It has been recognized that during chronic inflammatory systemic diseases (CIDs) maladaptations of the immune, nervous, endocrine and reproductive system occur. Maladaptation leads to disease sequelae in CIDs. The ultimate reason of disease sequelae in CIDs remained unclear because clinicians do not consider bodily energy trade-offs and evolutionary medicine. We review the evolution of physiological supersystems, fitness consequences of genes involved in CIDs during different life-history stages, environmental factors of CIDs, energy trade-offs during inflammatory episodes and the nonspecificity of CIDs. Incorporating bodily energy regulation into evolutionary medicine builds a framework to better understand pathophysiology of CIDs by considering that genes and networks used are positively selected if they serve acute, highly energy-consuming inflammation. It is predicted that genes that protect energy stores are positively selected (as immune memory). This could explain why energydemanding inflammatory episodes like infectious diseases must be terminated within 3–8 weeks to be adaptive, and otherwise become maladaptive. Considering energy regulation as an evolved adaptive trait explains why many known sequelae of different CIDs must be uniform. These are, e.g. sickness behavior/fatigue/depressive symptoms, sleep disturbance, anorexia, malnutrition, muscle wasting—cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal (HPG) axis, hypertension, bone loss and hypercoagulability. Considering evolved energy trade-offs helps us to understand how an energy imbalance can lead to the disease sequelae of CIDs. In the future, clinicians must translate this knowledge into early diagnosis and symptomatic treatment in CIDs. ", "ß The Author(s) 2016. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. " ]

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[ "K E Y W O R D S : inflammatory systemic disease; neuroendocrine immunology; energy regulation; disease sequelae ", "INTRODUCTION ", "Chronic inflammatory systemic diseases (CIDs) like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and many others are a burden to humans because of life-long debilitating illness, increased mortality and high costs for therapy and care. Other than CIDs, infectious disease like influenza or scarlet fever typically last only for a short period of time and they normally do not lead to chronic disease sequelae. The main difference between CIDs and acute infectious disease is span of time. While an acute infectious disease or inflammation during wound healing represents an adaptive response to overcome a disease and, thus, to increase life-time reproductive success, a CID is outside the adaptive reaction norm leading to maladaptive responses and a reduction of evolutionary fitness, because the stimulating trigger cannot be removed (for discussion of reaction norm see [1]). ", "CIDs are often discussed within the evolutionary medicine framework of the ‘hygiene hypothesis’ [2]. This model says that since the start of urbanization humans experienced a depletion of typical environmental infectious organisms such as helminths with which mammals co-evolved. The loss of these infectious agents provoked a change of normal background levels of immunoregulation during infancy, and this stimulated a more aggressive immune response in adulthood and old age and, thus, more frequent appearance of CIDs [2]. ", "An approach of evolutionary medicine to CIDs is needed because of the fact that CIDs exist although they exert a negative effect on reproductive fitness [3–9]. So far, the persistence of CIDs was partly explained by the important roles a limited number of networked immune system genes play in pathogen defense and other functions that are under strong natural selection [10]. While these previous theories focused on the trigger of CIDs, here we extend this by focusing on common disease pathways and sequelae of CIDs. ", "Coordinated reactions of the supersystems (immune, nervous, endocrine and reproductive) that maintain homeostasis have been evolutionarily conserved to respond to and eliminate foreign agents over a period of days to a few weeks (e.g. influenza or scarlet fever) [11]. If the responses of ", "these supersystems fail to return to normal such as in autoimmunity or other forms of systemic chronic inflammation (e.g. autoinflammatory syndromes), maladaptation of the supersystems perpetuates long-lasting CIDs [11, 12]. Since 2003 this theory has been refined, because new theoretical concepts from the field of bodily energy regulation were added [13–15]. This addition improved the model that is presented here in an updated version. ", "EVOLUTION OF THE SUPERSYSTEMS AND THEIR INTERACTIONS ", "Infectious and non-infectious hazards were present throughout the entire evolutionary history of all vertebrates including humans. With rats and mice, we share many similar inflammatory mechanisms, although the last common ancestor lived 65 million years ago [16]. Humans and chicken use immunoglobulin gene rearrangement and somatic hypermutation to shape the antibody response towards infectious agents [16]. Even sharks have a very similar immune system like ours with T cell receptors and immunoglobulin diversity based on V(D)J recombination and the RAG1/2 system [17]. Differences only become apparent when comparing humans with jawless fish (lampreys and hagfish; the last common ancestor with humans lived 460 million years ago), which use a more primitive immune system which, nevertheless, already consists of variable lymphocyte receptors [17]. ", "Thus, when we study the activation of the immune system in the context of the most prevalent danger of infection, we have to consider that the evolutionary history of the human immune system spans more than 420 million years. The immunological pathways are conserved and are very similar between sharks, birds, rodents and humans. In sum, acute inflammation is an adaptive response present in nearly all vertebrates, which has evolved to cope with infections or short-lived inflammatory responses (e.g. wound healing or foreign body reactions). ", "In a similar way, fish, birds, rodents and humans share many neuroendocrine pathways responsible for bodily homeostasis such as the hypothalamicpituitary-adrenal axis (HPA) axis or the sympathetic nervous system. For example, glucocorticoids of the " ]

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[ "HPA axis are present in mammals, birds, jawed fish and even in lamprey [18, 19]. ", "The bilaterally organized sympathetic nervous system is present in jawed fish like sharks and rays and in all vertebrates, but it is absent in lampreys and hagfish [20]. Nevertheless, lampreys produce catecholamines in monoamine-containing neurons, which also happens in leukocytes in the human body [21, 22]. Even bacteria possess functional orthologs of tyrosine hydroxylase, which converts L-thyroxine to L-DOPA, the first catecholamine in the synthesis cascade towards noradrenaline and adrenaline and bacteria use catecholamines as growth factors [23, 24]. ", "In addition, central nervous system responses such as sickness behavior [25] or anorexia [26] are similar in birds and rodents, indicating long evolutionary history. Rainbow trouts can become anorectic under stressful conditions [27]. Even crocodiles develop anorexia and lethargy during infection [28], which demonstrates the uniformity of the response. In sum, the immune, endocrine, and nervous systems have evolved over hundreds of millions of years, and to understand diseases in humans, including CIDs, the long evolutionary history of these supersystems has to be taken into account. ", "When we observe crosstalk between the supersystems, many similar pathways are used in humans and other vertebrates to maintain homeostasis. If homeostasis is disturbed by stressful events such as infection (leading to inflammation), the different supersystems need to cooperate in order to overcome the threat. The crosstalk of supersystems has co-evolved with infectious agents. Importantly, such a reaction to inflammatory stress is relatively uniform in many species. Genes enabling a coordinated response of the supersystems, allowing the organism to overcome infection or wounding, will increase survival probability and the potential for future reproduction and—as such—evolutionary fitness. ", "EVOLUTIONARY FITNESS AND CIDs ", "It can be expected that CIDs lead to reduced evolutionary fitness by indirect and direct effects. First, affected individuals would have reduced competitive abilities, reducing their access to resources such as food and sexual partners, and their social status in the group might be impaired. There might be even active repudiation in the group. In our ancestors, the risk of injury or even death in any competition including fights and warfare as well as encounters ", "with predators would have significantly increased due to their handicap. ", "Second, CIDs directly influence reproductive success by decreasing fecundity [3–9]. Even with optimum treatment in our days, fertility is reduced in both men and women with CIDs [29]. CIDs are accompanied by a severe decrease of androgen levels [30–32], which can be observed even after subcutaneous injection of the proinflammatory cytokine interleukin-6 (IL-6) into healthy volunteers. IL-6 blocks the release of testosterone by \u001850%, and it needs 7 days until restoration of normal serum levels [33]. In the acute phase of inflammatory diseases, IL-6 is nearly always increased and, thus, affects sexual function and sex hormone release. During a CID, this cytokine remains elevated if no appropriate treatment is applied. ", "There the proinflammatory TNF directly inhibits gonadal cells responsible for testosterone secretion [34]. Injection of another inflammatory cytokine, IL-1b, into the brain of experimental animals decreased testosterone production for a long time [35]. The same cytokines influence sperm motility resulting in reduced mucosal penetration properties and decreased male fertility female reproduction is influenced by inflammatory cytokines such as IL-1 and TNF [37, 38], and infectious episodes reduce female fertility [39]. Inflammation has deleterious effects on the menstrual cycle, leading to amenorrhea [40]. Thus, the reproduction system is switched-off in both sexes during inflammation. [36]. Similarly, evidence other clear that is ", "From a point of view of evolutionary history, it can be expected that the disease itself lead to early death in our ancestors, because no appropriate therapies were available until the 1950s. All conditions imply a high negative selection pressure for specific genetic factors leading to CIDs, especially, if these would have occurred in young reproducing adults. ", "GENETICS AND ENVIRONMENTAL INFLUENCE IN CIDs ", "Accumulation theory of CIDs ", "Natural selection cannot favor any chronic disease, because of the associated fitness costs and absence of any fitness gains. However, an individual that would suffer from a CID at a post-reproductive life history stage might have transmitted genes— increasing the risk to develop a chronic illness in late " ]

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[ null, "The respective single nucleotide polymorphism in the mentioned genes have been found in genome-wide association studies [42]. The list is ordered according to the significance level of the statistical test for relative risk. HLA, human leukocyte antigen; IL, interleukin; TNF, tumor necrosis factor. ", "age—during an earlier life history stage when it was healthy and reproducing. ", "Several genes that play a role in CIDs have been identified. The best know association between CIDs and genes has been established for the HLA system, which is an important element of antigen presentation. Sometimes the risk to develop a disease in presence of a certain subtype of the HLA system can be high. Approximately 10–25% of humans carry risk HLA genotypes but the prevalence of any of the CIDs is 0.1–1% [41], and thus, far below the expected 10–25%. Thus, there have to be additional factors and a certain HLA protein alone is not necessary and not sufficient to elicit a certain CID. ", "Today we label such an alteration as a genetic disease-promoting risk factor. As the alteration of an HLA protein is not the single causative factor, we expect that other genetic factors and the environment (see below) are also relevant. Indeed, CIDs have a multifactorial genetic background as demonstrated, e.g. in rheumatoid arthritis [42]. Many additional genetic factors have been described that increase the risk to develop rheumatoid arthritis (Table 1). Therefore, negative selection for specific HLA gene variants most probably was small, because in most individuals carrying the gene the disease did not develop due to the lack of additional factors. In contrast, polymorphic HLA genes have been retained because they helped to overcome various infections [43], leading to positive selection. The ", "genetic prerequisites for a CID can be retained over generations and generations via individuals that never express the disease because relevant cofactors may either not occur or are expressed following very irregular patterns. ", "Table 1 demonstrates that the same signaling factors can play a role in different CIDs such as multiple sclerosis (TYK2, CD40, TNFAIP3, PTPN22, IL-2, IL2RA and others; ref. [44]), type 1 diabetes mellitus (TNFAIP3, PTPN22, IL-2, IL-2RA, SH2B3 and others, refs. [45–47]), systemic lupus erythematosus (TYK2, TNFAIP3, PTPN22, FCGR2B, reviewed in ref. [48]), and Crohn’s disease (TYK2, PTPN22, IL-2RA, ICOSLG and others, ref. [49]). This tells us that the same immunostimulatory or immunoinhibiting signaling pathways are used in the different diseases. These shared immune factors have been positively selected in the context of infectious diseases but not for CIDs (see next section ‘Pleiotropy theory of CIDs’, ref. [10]). ", "In addition, accumulation of different risk alleles does not only lead to additivity of risk but to synergistic effects as demonstrate for the R620W PTPN22 allele and ‘HLA-DRB1 shared epitope’ alleles in rheumatoid arthritis [50]. In addition, African Americans positive for ‘HLA-DRB1 shared epitope’ alleles have a higher risk of developing rheumatoid arthritis when they demonstrate a higher degree of European ancestry, which demonstrates genetic admixture [51]. " ]

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[ "Table 2. Concordance rate in twin studies in chronic inflammatory systemic diseases ", null, "From monozygotic twin studies, it is known that genes contribute to the appearance of CIDs (Table 2). In these twin studies, the concordance rate has been determined as the quantitative statistical expression for the concordance of a given genetic trait. The concordance rate varies between 0 and 50%, and is on average 25% for the mentioned CIDs in Table 2, indicating that the environment explains \u001875% of the variation. Thus, considering gene-environment interactions is of outstanding importance. The accumulation theory describes how the accumulation of several genetic and environmental risk factors increases the risk to develop a CID. ", "and increased serum levels An interesting example for an environmental factor affecting the risk to develop CIDs is smoking. Already in the 1970s, a link was demonstrated between smoking of autoantibodies [58]. The first epidemiological studies on the link between smoking and the risk to develop rheumatoid arthritis appeared in the early 1990s [59– 61]. One study on monozygotic twins showed that smoking increased the risk to develop rheumatoid arthritis by a factor of 12 [62]. The risk remains elevated for several years after smoking cessation [63]. This demonstrates that smoking is a very strong environmental risk factor, and Lars Klareskog et al. showed that smoking may trigger HLA-DR-restricted immune reactions to autoantigens modified by citrullination [64]. Importantly, smoking is also linked ", "to an increased risk to develop other CIDs such as ankylosing spondylitis [65], multiple sclerosis [66], Crohn’s disease [67] and systemic lupus erythematosus [68, 69]. However, smoking can also reduce the risk of developing CIDs such as type 1 diabetes mellitus [70], ulcerative colitis [67] or pemphigus [71]. ", "There are several other environmental factors that are known to affect the development pf CIDs. For example, alcohol can protect individuals from developing rheumatoid arthritis [72]. Intake of oily fish was associated with a modestly decreased risk of developing rheumatoid arthritis [73]. Another environmental risk factor for rheumatoid arthritis and other autoimmune diseases is silica exposure, which occurs in construction work (cement, demolition) [74, 75]. It was discussed that silica is a stimulator of the immune system, which may trigger the autoimmune process leading to chronic inflammation [74, 75]. These examples clearly demonstrate that environmental factors play an important role, supporting the accumulation theory. ", "Another environmental modulator is the microbiota in the gut and elsewhere on body surfaces. Over millennia of co-evolution, microbiota has been a strong stimulus for shaping the innate and adaptive immune system in vertebrates [76]. During evolution, responses towards microbes have established a finetuning of immune responses [43]. We expect that microbiota-reactive T and B lymphocytes support homeostasis of the body [76]. Thus, normal microbiota or changes in microbiota during disease states or continuous illness can modulate the expression of CIDs. The famous example of HLA-B27 transgenic rats clearly shows the phenomenon: these rats develop arthritis and colitis in the presence of microbiota but are protected in a germ-free environment [77]. Thus, microbiota can be a decisive environmental factor, and new studies suggest possible causal links between microbiota and CIDs [78]. ", "Pleiotropy theory of CIDs ", "George C. Williams, an evolutionary biologist studying aging [79], stated in 1957: ", "It is necessary to postulate genes that have opposite effects on fitness at different ages, or, more accurately, in different somatic environments. ", "This theory is now widely accepted in aging research and elsewhere, and it is called ‘antagonistic pleiotropy theory’. The word pleiotropy comes from the Greek pleio, meaning ‘many’, and trepein, " ]

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[ "Table 3. Examples of antagonistic pleiotropy for genes that increase risk or severity of chronic inflammatory diseases [80] ", null, "meaning ‘influencing’. Pleiotropic means that genes can influence different phenotypic traits at different life history points. We propose that the same theory applies to the situation in CIDs, with genes being adaptive at an early age, but maladaptive at older age (another somatic environment), leading to an overall increase in Darwinian fitness, even though causing disease and suffering at older age (Table 3). ", "It can be expected that all genes associated with CIDs were positively selected because they confer fitness benefits by improving reproduction, stronger skeletal muscles, better storage of energy-rich fuels (in fat tissue), or better fight-and-flight responses (stronger activation of the sympathetic nervous system and HPA axis). However, a gene or allele increasing reproductive success in early adult life can play a deleterious role in an elderly person suffering from a CID, and still overall increase Darwinian fitness. For example, a gene may confer an excellent immune response against infectious agents because it leads to a stronger activity of immune cells or better bacteria/virus recognition. This gene is advantageous in younger ages because the gene carrier has less childhood infections and, thus, a higher chance to survive until reproductive age. However, the immune system of the gene carrier might be over-activated later in life, leading to the ", "development of a CID. However, this cost at late age (often in post-reproductive life history stages) would be much lower than the benefit of increased chance of survival until reproduction. ", "Let us make another example from the endocrine world. It is widely accepted that the incidence rate of rheumatoid arthritis in women largely increases after menopause [89] (Fig. 1). Women with an early onset of menorrhoea, with shorter cycle lengths and higher numbers of ovulatory cycles have an increased risk of early menopause [90, 91]. In order to understand this phenomenon, one has to recall that ovaries are equipped with a limited number of oocytes, and, with every ovulation, oocytes are released and the remaining number decreases gradually. Under consideration of an early onset of menorrhoea and shorter ovulatory cycles, more oocytes will be released until age 40. ", "The occurrence of menorrhoea and premature adrenarche has a strong genetic component [92]. Under some environmental conditions, the carrier of this trait should reproduce earlier and more often, thereby, increasing reproductive success. However, this trait also causes earlier menopause, increasing the risk to develop the CID rheumatoid arthritis [59, 89], but the cost of developing this CID might be low compared to the fitness benefits of early and " ]

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[ null, "Figure 1. Incidence rate of rheumatoid arthritis (RA). The black line indicates the normal situation with a menopause starting at 45 years of age. The red line demonstrates a fictitious situation with accelerated menopause years before ", "frequent reproduction. Thus, a gene conferring an early onset of menorrhoea that might be favorable for sexual function and reproduction early in life, would lead to early menopause and an earlier onset of rheumatoid arthritis (red line in Fig. 1) [59]. In addition, RA patients with an earlier onset of menopause have a more severe disease with more pain and positive rheumatoid factors [93]. ", "The link between the HLA system, infection, and sets of secreted cytokines was nicely summarized by Chella David’s group of the Mayo Clinic [43]. This investigation demonstrated that cytokine sets are related to different types of infectious immune stimuli. A more clinical example is given in a Mexican population. It was demonstrated that the genetic risk factor HLA-DR4 (DRB1*04), known to be positively associated with rheumatoid arthritis and other CIDs, is highly negatively associated with the risk of dengue hemorrhagic fever [81]. HLA-DR4 (DRB1*04) homozygous individuals were 11.6 times less likely to develop dengue hemorrhagic fever in comparison to DR4(DRB1*04) negative persons, demonstrating that the genetic factor HLADR4 (DRB1*04) is protective against this infectious disease [81]. Since we are all descendants of African Homo sapiens, dengue was relevant to the entire human population some 100 000 years ago when humans lived in warmer climates. Thus, it seems that HLA-DR4 (DRB1*04) has been evolutionarily positively selected to fight off dengue hemorrhagic fever and other microbes in early life but later in old age supports the development of a CID. This leads to life-time reproductive success by its action in early life, even though imposing costs by increasing the risk to develop CIDs at late age. ", "Another example is the Fc-gamma receptor IIIA, which is responsible for the recognition of immunoglobulin G leading to immune cell activation. The recognition of immunoglobulin is important to ", "for detect bacteria and viruses, which are bound to immunoglobulin G (opsonization and phagocytosis). After binding to the cell surface Fc-gamma receptor IIIA, immunoglobulin G together with bacteria or viruses are taken up, and the cell gets stimulated to destroy the microbe. However, one form of the Fc-gamma receptor IIIA, with a genetic polymorphism in position 158, being homozygous for the amino acid valine (158 valine/valine), has a higher binding affinity immunoglobulin G when compared to other Fc-gamma receptors [94], and this is associated with a higher risk to develop rheumatoid arthritis [95]. Importantly, the 158 valine/valine variant seems to protect against poliomyelitis [82], which indicates that this receptor variant confers protection against viral disease. Again, it seems that the genotype 158 valine/valine of the Fc-gamma receptor IIIA has been evolutionarily positively selected to fight off infectious agents by increasing microbe clearance. This trait is most advantageous in early ages (infants and young adults) by increasing the chances to reproduce, but the same surface molecule assists the development of a CID in older ages. ", "such as Pleiotropy occurs when a single gene influences multiple phenotypic traits. Such a gene can be largely advantageous for the carrier in earlier years in reproductive time, but it can also be highly disadvantageous in later ages in another somatic environment aging [79] or CIDs. These considerations might open our eyes when we study genetic risk factors in patients with CIDs. It also explains why a risky gene polymorphism is most probably not specific for a given CID, because the gene was evolutionarily positively selected for a different function. ", "IMMUNE RESPONSE, ENERGY CONSUMPTION VERSUS PROTECTION and CIDs ", "In a previous review, it was argued that a highly activated immune/repair system should not be switched on for a long time because this would be very energy-consuming [14]. Additionally, a highly activated immune system is accompanied by sickness behavior and anorexia, which prevents adequate food intake and necessitates life on stored reserves (inflammation-induced anorexia). Under systemic inflammatory conditions, breaking down all reserves takes 19–43 days [14]. An energy trade-off between immune system and other bodily " ]

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[ "systems explains this time-point, and this time-point also explains when inflammation becomes maladaptive and chronic (like in CIDs) [14]. ", "A highly activated immune/repair system can need huge amounts of energy. For example, the energy consumption in the case of extensive burn wounds (up to 20 000 kJ/day [4777 kcal/day]) [14] is approximately the same as during military jungle training (also 20 000 kJ/day; ref. [96]), and more than during military arctic training (\u001818 000 kJ/day; ref. [97]). Although burn wounds represent the extreme end of the spectrum, it demonstrates the high energy consumption of the immune system (another number on energy expenditure of the immune system is 15 000 kJ/day in sepsis). Energy is a limited resource for all vertebrates, a key determinant of survival and reproduction. ", "Energy consumption and energy storage are some of the most critical determinants in evolution [98]. If alterations of homeostasis lead to the selection of physiological mechanisms characterized by very high energy consumption, then the situation cannot be chronic—it must be acute. Such situations lead to allostatic overload type I, which means that energy consumption is higher than energy intake, which occurs during emergency life history stages [98]. Since time to total consumption of stored energy is \u001819–43 days [14], an acute energy-consuming change of homeostasis must be started and terminated within this time frame, as otherwise permanent damage and finally death occur. ", "A very good example for this time window is the germinal center reaction of B cell expansion and contraction that happens within \u001821–28 days [99]. Most acute disease states are terminated within this time frame such as infectious diseases, wound healing, and wound repair, but also strong mental activation in catastrophic stressful situations must be terminated because they are highly energy-consuming [100]. During evolution, respective homeostatic networks of supersystems were positively selected for shortlived acute energy-consuming responses but not for long-standing polygenic CIDs or chronic mental illness. These chronic situations would have generated a strong negative selection pressure if they occurred during early life and during the reproductive life history stage. ", "In contrast, if mutations were helpful to protect energy reserves, they were positively selected during evolution. This is true for memory responses because immediate reaction of an educated system can spare energy reserves. This is exemplified by ", "the immune memory that leads to shorter, more effective and, finally, less energy-consuming reactions towards microbes. Importantly, acquisition of immune memory during the primary contact must fit into the above specified time frame of 19–43 days (and this happens as exemplified by the germinal center reaction in secondary lymphoid organs, ref. [99]). In this context, immunological tolerance versus harmless foreign antigens (e.g. of microbes on the skin) or harmless autoantigens is a memory function that spares energy reserves. ", "Another example of positively selected gene variants are genes for food intake and fat storage, both of which are important in determining abovementioned total consumption time. Indeed, for a female Australopithecus afarensis it has been estimated that the consumption time was \u001819 days, while in a modern female Homo sapiens it is 43 days [14]. In human evolution, fat storage has been markedly increased over the last 6 million years [101]. Not surprisingly, the latest metaanalysis of genome-wide association studies of obesity and the metabolic syndrome found polymorphisms in genes relevant for food intake such as FTO (fat mass and obesity related), MC4R (melanocortin receptor type 4), POMC (proopiomelanocortin, the precursor of melanocortin) and genes relevant for fat storage such as the insulin-stimulating GIPR (gastric inhibitory polypeptide receptor) [102]. ", "We explained these common signs and symptoms as a trade-off between energy allocation to the immune system versus distribution to the rest of the body. The immune system is selfish [103], because a fast and strong response is needed during infection to enable survival to future reproduction [104]. For example, inDrosophila melanogaster, which shares a common ancestor with us 530 million years ago, it was demonstrated that the immune system is selfish in the form that it requires a lot of energy which is then not available for other systems [104]. The authors described systemic changes in energy metabolism during an infectious immune challenge by extracellular adenosine. They found that extracellular adenosine, released from immune cells, induces a metabolic switch characterized by the suppression of nutrient storage and developmental growth in favor of the immune defense. This metabolic switch—a tradeoff between development and defense—is crucial for the resistance to infection. In Drosophila larvae lacking adenosine signaling, development is not suppressed and the resistance dramatically drops [104]. " ]

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[ "Table 4. Positively selected immune mechanisms under defined conditions of A) acute, highly energy-consuming responses terminated within 3–8 weeks and B) long-standing, energy-protective responses ", null, "The list is not complete. ", "In sum, genes relevant for functioning of the supersystems are positively selected to protect energy stores under well-defined conditions (Table 4). Immune mechanisms were positively selected for either acute, highly energy-consuming responses terminated within 3–8 weeks or long-standing, energy-protective responses. ", "MICROBIOTA, ENERGY REGULATION AND CIDs ", "Above, we mentioned that microbiota play an important role in HLA-B27 transgenic rats, which only develop CIDs when exposed to microbiota [77, 105]. Some discussed the influence of microbiota on development of CIDs simply as an unfortunate trigger of the innate and adpative immune systems leading to autoimmunity. However, microbiota also play an enormous role in metabolism and, thus, in energy regulation of the body [106, 107]. ", "In experimental animals, there exist causal links between gut microbiota and obesity, which demonstrates an influence on energy regulation [107]. Conventionally raised mice develop diet-induced obesity, while germ-free animals do not [106]. Some bacterial divisions seem to play an important role for obesity [107, 108]. The obesity-triggering microbiome has an increased capacity to harvest energy from the ", "diet [108], but it is also linked to more inflammation in the gut and liver [109, 110]. ", "One may speculate that some bacterial divisions are important in establishing a more proinflammatory milieu supported by a higher degree of energy stores (obesity) to overcome acute infectious illness (free fatty acids as energy-rich fuels). Thus, the change in the microbiome can be positive for short-lived inflammatory diseases. However, the chronic change of the microbiome towards these proinflammatory bacterial divisions might be accompanied by chronic inflammatory illness. One has to keep in mind that bacterial divisions are also relevant for immunoregulatory function. Thus, it needs to be determined which groups play a causal role in the course of a CID. ", "The ‘NON-SPECIFICITY’ of SIGNS AND SYMPTOMS IN CIDs ", "In medicine, usually, the signs and symptoms in CIDs are thought to be an accident of the disease. The ultimate cause of CIDs and typical disease sequelae is not known. Symptomatology appears to be baffling and there is no common denominator to explain often common systemic disease sequelae in CIDs. In addition, physicians still believe that many symptoms are specific for one or the other CID, which most often is not the case. " ]

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[ "Table 5. Common signs and symptoms in chronic inflammatory systemic ", null, "This list is not complete. HPG axis, hypothalamic-pituitary-gonadal axis. ", "At this point we recall that CIDs-related gene polymorphisms were not specifically selected for a given CID. In contrast, because of strong negative selection for these gene variants, natural selection would have outselected these genes. Thus, evolutionary medicine asks why these genes have not been outselected. In CIDs, which typically occur in a post-reproductive life history stage, uniform pathways and networks were positively selected as adaptive physiological mechanisms to deal with infections and wound healing in life history stages before or during reproduction (Table 4). We call this uniformity a non-specificity of CIDs. ", "This non-specificity is obvious in clinical medicine because symptoms in various infectious diseases ", "including CIDs are surprisingly similar. Think of the erythrocyte sedimentation rate, which most often climbs independent of the type of acute inflammation or CID. Or think of fatigue, which often accompanies acute inflammation or CIDs. Many more common signs and symptoms have been recently summarized (Table 5) [13, 14, 103, 111–113]. ", "We explained these common signs and symptoms as a trade-off between energy allocation to the active immune system versus the rest of the body. While the presence of these phenomena is useful for short-lived inflammatory episodes in order to optimise recovery (it is not accident), long-term use in CIDs of the same programs is maladaptive. " ]

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[ null, "Figure 2. There is a critical difference between typical inflammation and chronic inflammatory systemic diseases, which separates the asymptomatic phase from the symptomatic phase of a chronic inflammatory systemic disease, the asymptomaticsymptomatic-threshold (a-s-threshold). Importantly from an evolutionary point of view, reproduction is only impeded during the symptomatic, but not during the asymptomatic phase. Genes enabling an adaptive inflammatory response, allowing the organism to overcome an infection, will thus increase survival probability and the potential for future reproduction and as such evolutionary fitness in young age. After initiation of chronic systemic inflammation, however, reproduction is inhibited, and this for prolonged periods, often for years and until death, causing fitness costs. However, as these costs typically occur only at the end of the reproductive life-history stage or in post-reproductive age, these fitness costs are lower than the fitness benefits in early life leading to an overall increase in Darwinian fitness ", "CONCLUSIONS ", "CIDs lead to great and long-term suffering, imposing stress on people and high costs on society. During evolution, respective homeostatic networks of supersystems involved in CIDs were positively selected for short-lived acute energy-consuming responses but not for long-standing polygenic CIDs (Fig. 2). Several genetic factors of these supersystems that are favoring the development of CIDs have been identified. These factors typically increase fitness in young pre-reproductive and reproductive age, and resulting fitness benefits are expected to be higher than the fitness costs in post-reproductive age. Thus, lifetime reproductive success will be increased, explaining why factors favoring CIDs have not been outselected but—under specific environmental conditions—have selected. Different CIDs result from uniform pathways and networks, which has been called the non-specificity of CIDs. For clinicians and the pharmaceutical industry to understand maladaptive responses in CIDs, they first need to comprehend adaptive functions in early life. even been positively ", "funding ", "For this work, the authors were funded by their institutions. ", "Conflict of interest: None declared. ", "references ", "1. Stearns SC. The Evolution of Life Histories. Oxford: Oxford University Press, 1992. 2. Rook GA. Hygiene hypothesis and autoimmune diseases. Clin Rev Allergy Immunol 2012;42:5–15. 3. Soares PM, Borba EF, Bonfa E et al. Gonad evaluation in male systemic lupus erythematosus. Arthritis Rheum 2007;56: 2352–61. 4. Suehiro RM, Borba EF, Bonfa E et al. Testicular Sertoli cell function in male systemic lupus erythematosus. Rheumatology (Oxford) 2008;47:1692–7. 5. Silva CA, Deen ME, Febronio MV et al. Hormone profile in juvenile systemic lupus erythematosus with previous or current amenorrhea. Rheumatol Int 2011;31:1037–43. 6. Villiger PM, Caliezi G, Cottin V et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann Rheum Dis 2010;69:1842–4. 7. Richter JG, Becker A, Specker C et al. Hypogonadism in Wegener’s granulomatosis. Scand J Rheumatol 2008;37:365–9. " ]

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Evolutionary medicine and chronic inflammatory state – known and new concepts in pathophysiology. J Mol Med 2012;90:523–34. 15. Straub RH. Interaction of the endocrine system with inflammation: a function of energy and volume regulation. Arthritis Res Ther 2014;16:203–17. 16. Cortez D, Marin R, Toledo-Flores D et al. Origins and functional evolution of Y chromosomes across mammals. Nature 2014;508:488–93. 17. Rast JP, Buckley KM. Lamprey immunity is far from primitive. Proc Natl Acad Sci USA 2013;110:5746–7. 18. Ritchie M. Neuroanatomy and physiology of the avian hypothalamic/pituitary axis: clinical aspects. Vet Clin North Am Exot Anim Pract 2014;17:13–22. 19. Rai S, Szeitz A, Roberts BW et al. A putative corticosteroid hormone in Pacific lamprey, Entosphenus tridentatus. Gen Comp Endocrinol 2014;10 20. Funakoshi K, Nakano M. The sympathetic nervous system of anamniotes. Brain Behav Evol 2007;69:105–13. 21. Bergquist J, Tarkowski A, Ekman R et al. Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamine regulation of lymphocyte function via an autocrine loop. Proc Natl Acad Sci USA 1994;91:12912–6. 22. Miller LE, Ju¨sten HP, Scho¨lmerich J et al. The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. Faseb J 2000;14:2097–107. 23. Connor KL, Colabroy KL, Gerratana B. A heme peroxidase with a functional role as an L-tyrosine hydroxylase in the biosynthesis of anthramycin. Biochemistry 2011;50:8926–36. 24. Lyte M. Microbial endocrinology: Host-microbiota neuroendocrine interactions influencing brain and behavior. Gut Microbes 2014;5:381–9. ", "tion to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46–56. 26. Carter ME, Soden ME, Zweifel LS et al. Genetic identification of a neural circuit that suppresses appetite. Nature 2013;503:111–4. 27. Hoglund E, Sorensen C, Bakke MJ et al. Attenuation of stress-induced anorexia in brown trout (Salmo trutta) by pre-treatment with dietary l-tryptophan. Br J Nutr 2007;97:786–9. 28. Clippinger TL, Bennett RA, Johnson CM et al. Morbidity and mortality associated with a new mycoplasma species from captive American alligators (Alligator mississippiensis). J Zoo Wildl Med 2000;31:303–14. 29. Ostensen M, Almberg K, Koksvik HS. Sex, reproduction, and gynecological disease in young adults with a history of juvenile chronic arthritis. J Rheumatol 2000;27:1783–7. 30. Masi AT, Josipovic DB, Jefferson WE. Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA): gas-liquid chromatographic studies of RA patients and matched normal control women indicating decreased 11-deoxy-17-ketosteroid excretion. Semin Arthritis Rheum 1984;14:1–23. 31. Cutolo M, Balleari E, Giusti M et al. Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation. Arthritis Rheum 1988;31:1314–7. 32. Lahita RG, Bradlow HL, Ginzler E et al. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987;30:241–8. 33. Tsigos C, Papanicolaou DA, Kyrou I et al. Dose-dependent effects of recombinant human interleukin-6 on the pituitary-testicular axis. J Interferon Cytokine Res 1999;19: 1271–6. 34. Watson ME, Newman RJ, Payne AM et al. The effect of macrophage conditioned media on Leydig cell function. Ann Clin Lab Sci 1994;24:84–95. 35. Turnbull AV, Rivier C. Inhibition of gonadotropin-induced testosterone secretion by the intracerebroventricular injection of interleukin-1 beta in the male rat. Endocrinology 1997;138:1008–13. 36. Gruschwitz MS, Brezinschek R, Brezinschek HP. Cytokine levels in the seminal plasma of infertile males. 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[ "41. Cooper GS, Miller FW, Pandey JP. The role of genetic factors in autoimmune disease: implications for environmental research. Environ Health Perspect 1999;107(Suppl 5):693–700. 42. Okada Y, Wu D, Trynka G et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014;506:376–81. 43. Mangalam AK, Taneja V, David CS. HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile. J Immunol 2013;190:513–8. 44. Beecham AH, Patsopoulos NA, Xifara DK et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013;45:1353–60. 45. Plagnol V, Howson JM, Smyth DJ et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet 2011;7:e1002216 46. Bradfield JP, Qu HQ, Wang K et al. A genome-wide metaanalysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet 2011;7:e1002293 47. Barrett JC, Clayton DG, Concannon P et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009;41:703–7. 48. Rullo OJ, Tsao BP. Recent insights into the genetic basis of systemic lupus erythematosus. Ann Rheum Dis 2013;72(Suppl 2):ii56–61. 49. Franke A, McGovern DP, Barrett JC et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 2010;42: 1118–25. 50. Kallberg H, Padyukov L, Plenge RM et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 2007;80:867–75. 51. Hughes LB, Morrison D, Kelley JM et al. The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum 2008;58: 349–58. 52. Svendsen AJ, Holm NV, Kyvik K et al. Relative importance of genetic effects in rheumatoid arthritis: historical cohort study of Danish nationwide twin population. BMJ 2002;324:264–6. 53. Silman AJ, MacGregor AJ, Thomson W et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 1993;32:903–7. 54. Ringold DA, Nicoloff JT, Kesler M et al. Further evidence for a strong genetic influence on the development of autoimmune thyroid disease: the California twin study. Thyroid 2002;12:647–53. 55. Deapen D, Escalante A, Weinrib L et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992;35:311–8. 56. Duffy DL, Spelman LS, Martin NG. Psoriasis in Australian twins. J Am Acad Dermatol 1993;29:428–34. ", "tionwide series of twins. Arthritis Rheum 1995;38:381–3. 58. Mathews JD, Whittingham S, Hooper BM et al. Association of autoantibodies with smoking, cardiovascular morbidity, and death in the Busselton population. Lancet 1973;2:754–8. 59. Hernandez AM, Liang MH, Willett WC et al. Reproductive factors, smoking, and the risk for rheumatoid arthritis. Epidemiology 1990;1:285–91. 60. Heliovaara M, Aho K, Aromaa A et al. Smoking and risk of rheumatoid arthritis. J Rheumatol 1993;20:1830–5. 61. Voigt LF, Koepsell TD, Nelson JL et al. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis. Epidemiology 1994;5:525–32. 62. Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum 1996;39:732–5. 63. Stolt P, Bengtsson C, Nordmark B et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 2003;62:835–41. 64. Klareskog L, Stolt P, Lundberg K et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38–46. 65. Videm V, Cortes A, Thomas R et al. Current Smoking is Associated with Incident Ankylosing Spondylitis - The HUNT Population-based Norwegian Health Study. J Rheumatol 2014;41:2041–8. 66. Hernan MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol 2001;154:69–74. 67. Tobin MV, Logan RF, Langman MJ et al. Cigarette smoking and inflammatory bowel disease. Gastroenterology 1987;93: 316–21. 68. Ghaussy NO, Sibbitt WL Jr., Qualls CR. Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study. J Rheumatol 2001;28: 2449–53. 69. Hardy CJ, Palmer BP, Muir KR et al. Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study. Ann Rheum Dis 1998;57:451–5. 70. Carlsson S, Midthjell K, Grill V. Smoking is associated with an increased risk of type 2 diabetes but a decreased risk of autoimmune diabetes in adults: an 11-year follow-up of incidence of diabetes in the Nord-Trondelag study. Diabetologia 2004;47:1953–6. 71. Brenner S, Tur E, Shapiro J et al. Pemphigus vulgaris: environmental factors. Occupational, behavioral, medical, and qualitative food frequency questionnaire. Int J Dermatol 2001;40:562–9. 72. Kallberg H, Jacobsen S, Bengtsson C et al. Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case-control " ]

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[ "2009;20:896–901. 74. Parks CG, Conrad K, Cooper GS. Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect 1999;107(Suppl 5):793–802. 75. Khuder SA, Peshimam AZ, Agraharam S. Environmental risk factors for rheumatoid arthritis. Rev Environ Health 2002;17:307–15. 76. Peterson DA, Cardona RA. Specificity of the adaptive immune response to the gut microbiota. Adv Immunol 2010;107:71–107. 77. Taurog JD, Richardson JA, Croft JT et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994;180: 2359–64. 78. Zhang X, Zhang D, Jia H et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015;21: 895–905. 79. Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution 1957;11:398–411. 80. Straub RH. Neuroendocrine immunology: new pathogenetic aspects and clinical application. Z Rheumatol 2011;70:767–74. 81. LaFleur C, Granados J, Vargas-Alarcon G et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol 2002;63: 1039–44. 82. Rekand T, Langeland N, Aarli JA et al. Fcgamma receptor IIIA polymorphism as a risk factor for acute poliomyelitis. J Infect Dis 2002;186:1840–3. 83. McKiernan SM, Hagan R, Curry M et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology 2004;40:108–14. 84. Goulder PJ, Watkins DI. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 2008;8:619–30. 85. Pertovaara M, Raitala A, Juonala M et al. Autoimmunity and atherosclerosis: functional polymorphism of PTPN22 is associated with phenotypes related to the risk of atherosclerosis. The Cardiovascular Risk in Young Finns Study. Clin Exp Immunol 2007;147:265–9. 86. Thio CL, Mosbruger TL, Kaslow RA et al. Cytotoxic Tlymphocyte antigen 4 gene and recovery from hepatitis B virus infection. J Virol 2004;78:11258–62. 87. Raitala A, Karjalainen J, Oja SS et al. Helicobacter pyloriinduced indoleamine 2,3-dioxygenase activity in vivo is regulated by TGFB1 and CTLA4 polymorphisms. Mol Immunol 2007;44:1011–4. 88. Gu CC, Hunt SC, Kardia S et al. An investigation of genome-wide associations of hypertension with microsatellite markers in the family blood pressure program (FBPP). Hum Genet 2007;121:577–90. ", "observed age-sex interaction patterns support a role of androgenic-anabolic steroid deficiency in its pathogenesis? Br J Rheumatol 1994;33:697–9 90. Cramer DW, Xu H, Harlow BL. Does “incessant” ovulation increase risk for early menopause? Am J Obstet Gynecol 1995;172:568–73 91. Chang SH, Kim CS, Lee KS et al. Premenopausal factors influencing premature ovarian failure and early menopause. Maturitas 2007;58:19–30. 92. Roldan MB, White C, Witchel SF. Association of the GAA1013–>GAG polymorphism of the insulin-like growth factor-1 receptor (IGF1R) gene with premature pubarche. Fertil Steril 2007;88:410–7. 93. Wong LE, Huang WT, Pope JE et al. Effect of age at menopause on disease presentation in early rheumatoid arthritis: results from the canadian early arthritis cohort. Arthritis Care Res (Hoboken) 2015;67:616–23. 94. van de Winkel JG, Anderson CL. Biology of human immunoglobulin G Fc receptors. J Leukoc Biol 1991;49: 511–24. 95. Morgan AW, Keyte VH, Babbage SJ et al. FcgammaRIIIA158V and rheumatoid arthritis: a confirmation study. Rheumatology (Oxford) 2003;42:528–33. 96. Forbes-Ewan CH, Morrissey BL, Gregg GC et al. Use of doubly labeled water technique in soldiers training for jungle warfare. J Appl Physiol (1985) 1989;67:14–8. 97. Jones PJ, Jacobs I, Morris A et al. Adequacy of food rations in soldiers during an arctic exercise measured by doubly labeled water. J Appl Physiol (1985) 1993;75:1790–7. 98. McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav 2003;43:2–15. 99. Meyer-Hermann ME, Maini PK. Cutting edge: back to “one-way” germinal centers. J Immunol 2005;174: 2489–93. 100. Hitze B, Hubold C, van DR et al. How the selfish brain organizes its supply and demand. Front Neuroenergetics 2010;2:7–17. 101. Zihlman AL, Bolter DR. Body composition in Pan paniscus compared with Homo sapiens has implications for changes during human evolution. Proc Natl Acad Sci USA 2015;112:7466–71. 102. Fall T, Ingelsson E. Genome-wide association studies of obesity and metabolic syndrome. Mol Cell Endocrinol 2014;382:740–57. 103. Straub RH. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res Ther 2014;16(Suppl 2):S4 pages 1-15. 104. Bajgar A, Kucerova K, Jonatova L et al. Extracellular adenosine mediates a systemic metabolic switch during immune response. PLoS Biol 2015;13:e1002135 105. Rath HC, Herfarth HH, Ikeda JS et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 " ]

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[ "106. Janssen AW, Kersten S. The role of the gut microbiota in metabolic health. Faseb J 2015;29:3111–23. 107. Cox LM, Yamanishi S, Sohn J et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014;158:705–21. 108. Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesityassociated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–31. 109. Lam YY, Ha CW, Campbell CR et al. Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in dietinduced obese mice. PLoS One 2012;7:e34233 ", "110. Henao-Mejia J, Elinav E, Jin C et al. Inflammasomemediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012;482:179–85. 111. Straub RH. Concepts of evolutionary medicine and energy regulation contribute to the etiology of systemic chronic inflammatory diseases. Brain Behav Immun 2011;25:1–5. 112. Straub RH. The origin of chronic inflammatory systemic diseases and their sequelae. San Diego: Academic Press, 2015. 113. Straub RH, Cutolo M, Pacifici M. Evolutionary medicine and bone loss in chronic inflammatory diseases – a theory of inflammation-related osteopenia. Semin Arthritis Rheum 2015;45:220–8. " ]

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[ "The Reliability, Validity, and Normative Data of Interpupillary Distance and Pupil Diameter Using EyeTracking Technology ", "Nicholas P. Murray1, Melissa Hunfalvay2, and Takumi Bolte3 ", "1 East Carolina University, Greenville, NC, USA 2 Science Department, RightEye, LLC, Bethesda, MD, USA 3 Clemson University, Clemson, SC, USA ", "Translational Relevance: Results revealed a central point of fixation may remove variability in examining PD reliably using infrared eye tracking when consistent environmental and experimental procedures are conducted. ", "Purpose: The purpose of this study was to determine the reliability of interpupillary distance (IPD) and pupil diameter (PD) measures using an infrared eye tracker and central point stimuli. Validity of the test compared to known clinical tools was determined, and normative data was established against which individuals can measure themselves. ", "Methods: Participants (416) across various demographics were examined for normative data. Of these, 50 were examined for reliability and validity. Validity for IPD measured the test (RightEye IPD/PD) against the PL850 Pupilometer and the Essilor Digital CRP. For PD, the test was measured against the Rosenbaum Pocket Vision Screener (RPVS). Reliability was analyzed with intraclass correlation coefficients (ICC) between trials with Cronbach’s alpha (CA) and the standard error of measurement for each ICC. Convergent validity was investigated by calculating the bivariate correlation coefficient. ", "Results: Reliability results were strong (CA . 0.7) for all measures. High positive significant correlations were found between the RightEye IPD test and the PL850 Pupilometer (P , 0.001) and Essilor Digital CRP (P , 0.001) and for the RightEye PD test and the RPVS (P , 0.001). ", "Conclusions: Using infrared eye tracking and the RightEye IPD/PD test stimuli, reliable and accurate measures of IPD and PD were found. Results from normative data showed an adequate comparison for people with normal vision development. ", "Correspondence: Melissa Hunfalvay, Science Department, RightEye, LLC, 7979 Old Georgetown Rd, Suite 801, Bethesda, MD 20814, USA. e-mail: melissa@righteye.com ", "Citation: Murray NP, Hunfalvay M, Bolte T. The reliability, validity, and normative data of interpupillary distance and pupil diameter using eye-tracking technology. Trans Vis Sci Tech. 2017;6(4):2, doi:10.1167/ tvst.6.4.2 Copyright 2017 The Authors ", "Introduction ", "Distance between the pupils, called interpupillary distance (IPD), is an important clinical measure used to identify potential vision issues such as stereo acuity,1 near point convergence,2 accommodation,3 and other vision-related issues.4 Furthermore, normative IPD data is important in the optical industry when fitting patients for glasses. IPD is measured using the distance between the centers of the pupils.5,6 ", "Diameter of the pupil (PD) is another component of the eye that is measured and is related to image quality. A larger pupil will allow more peripheral rays ", "into the eye, resulting in high-order monochromatic aberrations that pose a problem with image quality when the PD is large.7 A limitation of very small pupils can be diffraction; however, this problem is less significant than the aberrations in larger pupil sizes as demonstrated by Howland and Howland.8 Depth of focus is related to pupil size. Smaller pupils allow an increase in depth of focus, which in turn reduces the effect of refractive errors and errors in accommodation such as accommodative lag on the quality (blur) of the retinal image.9 ", "Interpupillary distance and PD influence many vision components that are important in activities of daily living (ADLs) as well as peak performance in " ]

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[ "athletes and fighter pilots. For instance, IPD determines the amount of stereo separation of two images that are combined in the brain to produce stereo perception.10,11 Stereo perception is important in rapid three-dimensional processing involved in driving a vehicle and catching a ball. It is therefore important to be able to measure these metrics reliability and accurately and to determine normative data against which a person can be measured. ", "Numerous methods have been used in the measurement of IPD; Viktorins method, pupilometers, and corneal reflection are each commonly used in clinical settings. Viktorins method uses a hand measure of IPD by measuring the distance between certain features in the eye. Pupilometers are handheld ophthalmological devices that measure distance between the pupils by aligning the device with the corneal reflexes of the participant. Corneal reflection, the method used in the present study, measures the distance between the pupils through the reflection of infrared light on the eyes. ", "Various inaccuracies in these measurement processes have been discussed, including parallax error (a large difference between the IPD of observer and participant), incorrect spacing between the participant and the observer, and/or incorrect positioning of measurement tools.5 Obstfeld and Chou12 examined nine of the leading pupilometers and found an average of 2.3-mm error (SD ¼ 0.26 mm). Sources of error were poor eye relief in all pupilometers and friction in the scale adjustments. However, the pupilometers were found to give consistent readings (i.e., were reliable) within the limits of clinically acceptable parameters. However, the accuracy (i.e., the validity) was questioned, especially in IPDs that were especially large or small. Viktorins method and pupilometer measurements have been criticized for lack of examination of reliability, and in the few studies where reliability has been examined, results have revealed poor reliability.5 One possible reason for low reliability may not reside in the instruments themselves but in the technician’s difficulty using such instruments.13 ", "Numerous methods have been used in the measurement of PD, such as lens systems with millimeter scales (e.g., Colvard; Oasis Medical, Glendora, CA); dynamic and binocular PD measurements using infrared light (e.g., P2000SA; Procyon Instruments, London, UK); and wavelength aberrometers based on the Hartmann-Shack principle (e.g., WASCA; Asclepion-Meditec-Zeiss, Jena, Germany). In a study by Schmitz et al.,14 pairwise comparison between the lens ", "systems, infrared light, and wavelength aberrometers showed statistically significant (P , 0.05) differences in median deviations. Authors argue, however, that these differences (ranging up to 1 mm) were not clinically significant. ", "The form of comparison method employed by the Rosenbaum Pocket Vision Screener (RPVS) was first described in 1863 by Follin.15 It is still a widely used method of measuring pupil size in clinical practice.16 It is a low-cost alternative to the lens systems, infrared systems, and aberrometers. The RPVS is a commonly used tool for nonsurgical patients.17 to measure pupil diameter (PD) ", "Pupil diameter has also been measured using infrared eye trackers18 (e.g., Tobii X120, Tobii T120; Tobii Technology, Stockholm, Sweden, and Eye Link 1000; SR Research, Kanata, Canada). Brisson et al.18 found that pupil size can be overand underestimated in infrared eye trackers depending on gaze position. When the eyes are positioned straight ahead, the pupil is most accurately measured, ranging from 0.3 to 1.0 mm, depending on the eye tracker, with the Eye Link 1000 producing the best results. When the eyes look away from the center, systematic errors occur in measuring PD as the pupil appears squashed. When looking straight ahead, the pupil appears circular, therefore providing the most accurate PD readings. When using a chin–forehead rest, results were even more accurate (,0.3 mm). Nevertheless, the reliability (repeatability) and validity (accuracy) is questionable and requires further examination of both the tool and the stimuli used to examine the PD readings before results can be considered with confidence. ", "Interpupillary distance and PD differ based on various demographic considerations. Dodgson10 used data from the Anthropometric Survey of United States Army Personnel database, consisting of 3976 participant, aged 17–51, and investigated population norms for IPDs. Dodgson suggested that although a mean IPD of the population was proposed as 63.36 mm, this value was inaccurate when analyzed for ethnicity, sex, and age. Significant differences were identified between ethnic groups for mean IPD, which was attributed to various physiological differences among ethnicities. Sex differences were also found, with males demonstrating significantly greater IPDs than females.6,10 Interpupillary distance has also been shown to change significantly with age until approximately 30 years of age, with most change occurring in life.19 Given that IPD is the first 19 years of influenced by ethnicity, sex, and age, it would appear " ]

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[ "prudent that these characteristics be identified within research to avoid inconsistent results due to potential confounding variables. Pupil diameter has also shown to vary based on age,20,21 sex,22 and ethnicity.23 ", "The purpose of this study was to (1) determine the reliability of IPD and PD measures using an infrared eye tracker (120 Hz; TeHow, Germany) and central point stimuli (designed by RightEye, LLC, Bethesda, MD); (2) to examine the validity of the RightEye IPD Test compared to the PL850 Pupilometer (Hilco, Plainville, MA) and the Essilor Digital CRP (DAES03-001; Essilor, Charenton-le-Pont, France) for IPD, and the RPVS for PD measures (3908 Pocket Eye Chart; Medisave, Stratford, CT); (3) to establish normative data for which individuals can measure themselves. ", "Methods ", "Participants ", "Four hundred sixteen participants were selected for this study. Participants were recruited through advertisements placed on the internet, social media, bulletin boards, and via word of mouth. Of the group, 189 (45%) were males and 227 (55%) females. Participants were between the ages of 18 and 73 years (M¼ 42, SD¼ 8.7). Of the 416 participants, 68% were white, 17% black, 8% Hispanic, 1% Native American, and 6% opted not to report ethnicity. ", "To test reliability and validity, a small subgroup of 50 participants was tested a second time. The subgroup included participants between the ages of 24 and 73 years (M¼ 45, SD¼ 8.4); 48% were male (n ¼ 24), and 52% were female (n ¼ 26). Of the 50 participants, 70% were white, 15% black, 9% Hispanic, 0% Native American, and 6% opted not to report ethnicity. ", "Participants were excluded from participation in the study if they met any of the following prescreening conditions: neurological disorders (such as concussion, traumatic brain injury, Parkinson’s disease, Huntington’s disease, cerebral palsy); obvious vision-related issues that prevented successful calibration24,25 of all nine points (such as extreme tropias,26 phorias,26,27 static visual acuity of greater than 20/ 400,24 nystagmus,24,28 cataracts,29 or eyelash impediments29); small vessel strokes; or consumption of drugs or alcohol within 24 hours of testing. Participants removed any eyewear, including glasses or contact lenses. All participants provided informed consent to participate in this study in accordance with ", null, "Figure 1. (A) RightEye set up. (B) Magnification of eye tracker. ", "institutional review board procedure (IRB: UMCIRB 13-002660). This research followed the tenets of the Declaration of Helsinki. ", "Testing was conducted by vision specialists (e.g., optometrists, ophthalmologists) and, in the case of the RightEye IPD/PD test, the examiners had received and passed the RightEye training, education, and protocol procedures prior to testing. ", "Materials and Equipment ", "For the RightEye IPD/PD test, the participants were seated in a stationary (nonwheeled) chair that could not be adjusted in height at a desk within a quiet, private testing room (see Fig. 1). The participants were asked to look at a NVIDIA 24-inch 3D Vision monitor (NViDiA, Santa Clara, CA) that could be adjusted in height and was fitted with an SMI 12’’ 120-Hz remote eye tracker connected to an Alienware gaming system (Miami, FL) and a Logitech (Y-R0017; Logitech, Romanel-sur-Morges, Switzerland) wireless keyboard and mouse. Screen " ]

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[ null, "Figure 2. Stimuli. ", "luminance was 85 cd/m2 (229 lux), and room luminance with the lights on was 344 cd/m2 (102 lux). Participants’ heads were unconstrained during the test, although they were instructed to sit still. The system has no restrictions in range when calculating IPD or PD. ", "The eye tracker is used to capture the x and y coordinates for each eye, along with the z-distance at 120 times a second. Once the stimulus is at the center point of the screen (960 3 540), the eye tracker detects if the eye is looking at the stimuli; once confirmed, the first sample of data is used to measure IPD. Then, using the x and y eye coordinates in three-dimensional space, participants’ IPD is calculated for the left and right eyes. ", "Pupil diameter measurements are taken at the same time as IPD measurements in the RightEye IPD/PD test. For a 120-Hz eye tracker, output is reported every 8 milliseconds. Using the center point of the screen, 700 milliseconds of data are collected, resulting in a sample of 87 data points. These metrics are then used to calculate average pupil size, range, and standard deviation of both left and right eye. Size of the pupil is determined by the contour of the pupil. ", "PL850 Pupilometer ", "This digital pupilometer measures distance between the center of each pupil. Range is from 47 to 84 mm in 0.5mm steps. ", "Essilor Digital CRP ", "This corneal reflection pupilometer measures distance between the center of each pupil. Range is from 48 to 77 mm in 0.5-mm steps. ", null, "Figure 3. RightEye IPD/PD report. ", "Rosenbaum Pocket Vision Screener ", "The RPVS is a pupil size chart (16 3 9 cm) that measures pupil size in millimeters ranging from 2 to 9 mm. Pupil measurements were made at 1.0-mm steps unless the pupil appeared between two circles on the card, and a 0.5-mm measurement interval was made. ", "Testing Procedure ", "The RightEye IPD/PD test involved participants positioning themselves in front of the eye-tracking system, measured at an exact distance of 60 cm (ideal positioning within the head box range of the eye tracker) from the eye tracker for standardization before testing. A nine-point calibration test was conducted with points spanning the computer screen. Participants were required to pass all nine points before proceeding with testing. ", "Upon successful calibration, the RightEye IPD/PD test commenced. The participants read the following instructions: ‘‘Follow the dot from the top of the screen to the center. Watch the dot get smaller and keep looking at it until it disappears. Keep your eyes as still and focused when the dot stops in the center of the screen.’’ Binocular viewing conditions were used for testing, that is, data are collected simultaneously from the right and left eye. When instructions are read, the participant proceeds to the test where a dot drops from the top center of the screen to the middle of the screen (see Fig. 2). Once in the middle of the " ]

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[ "Table 1. Normative Data for RightEye IPD ", null, "SD ¼ standard deviation; Min¼ minimum; Max ¼ maximum; SEM¼ standard error of the mean; CI¼ confidence interval. ", "screen the dot stops and shrinks in size over a 700millisecond period. ", "At the conclusion of the test, a report showed both the IPD and PD results (see Fig. 3). ", "Participants assigned to the reliability group were then tested a second time using the same procedure as previously described. Time between tests was less than 1 minute. ", "Participants assigned to the validity group were administered the other clinical tests (RPVS, Essilor Digital CRP, PL850 Pupilometer). For measurement of IPD, the recommended steps outlined in each manual were used. ", "When using the PL850 and the Essilor Digital CRP, the pupilometer was first turned on. A target distance of 60 cm was set, and measurements were done monocularly. The participant was then instructed to hold the pupilometer up to the eyes the same way one would hold binoculars and to make sure the nose was on the nose rest. The participant was instructed to stare at the red dot through the view windows. Using the left and right eye control buttons, the examiner slid the vertical PD lines over the participant’s retinal reflections (the pinpoint of light located inside the pupil). Then once satisfied with each measurement, the ‘‘hold’’ button was pressed to store the readings. ", "For measurement of PD, participants were requested to sit 60 cm from the computer screen, facing the investigator. The computer screen was not used for the test; however, the luminance from the screen was important to ensure the same conditions as the RightEye IPD/PD test. Computer screen luminance was 85 cd/m2 (229 lux), and room luminance with the lights on was 344 cd/m2 (102 lux). The investigator then held up the RPVS. The card was held temporal to the participant’s eye in the corneal plane. The examiner matched the horizontal PD with the appropriate circle. This procedure was conducted for each eye. ", "Participants were administered the RPVS, Essilor ", "Digital CRP, PL850 Pupilometer, and RightEye IPD/ PD test in random order. Participants were randomly assigned to a group to test either reliability or validity of the RightEye IPD/PD test. ", "Validity by Design ", "Validity by design, also considered face validity or priori validity, determines whether the test measures what is being claimed. The RightEye IPD/PD test has several validity by design elements build into the test. These fall into two categories: (1) test stimuli and (2) testing protocol. ", "Test Stimuli ", "To obtain accurate IPD, the stimuli must be presented in the center of the screen without deviation from one test to the next. This is obtained through computer programming, allowing the participant to see exactly the same stimuli every time the test is conducted. Furthermore, the stimuli (movement), time, and size reduction of the stimuli encourages the participant to look at the stimuli during the test. the initial drop of ", "To obtain accurate PD, the luminance level on the screen must remain consistent both during the test and between tests. To ensure this occurs, luminance is preset via software code to prevent any adaptations by a participant or tester. ", "Test Protocol ", "To ensure accuracy of IPD and PD it is important that three conditions are met: (1) distance from the screen is 60 cm, (2) the eyes remain stationary during the last 700 milliseconds, (3) the participant looks at the stimuli. To assist with these conditions a chin rest is recommended for younger patients or those with certain movement-related disorders. Additionally, error handling is employed using the eye tracker to determine the location of the participants’ eyes on the screen, ensuring they are looking at the target during the last 700 milliseconds when IPD and PD are being " ]

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[ "Table 2. Normative Data for RightEye PD ", null, "Reliability IPD: ICC were statistically significant at the P , 0.001 level (r ¼ 0.999). SD ¼ standard deviation; Min ¼ minimum; Max ¼ maximum; Var ¼ variance; CI ¼ confidence interval. ", "calculated. If this does not occur, an error message will let the tester know, and the test will be redone. This further enhances the confidence that the participant was confirmed as ‘‘on the stimuli’’ target when the calculations were made. ", "Hippus is the spasmodic or rhythmic contraction of the eye and is an important the pupil of consideration in both the development of stimulus and the metrics that report the results. Several parameters are in place, in consideration of hippus, to provide accurate results, rather than one point of fluctuation. First, many data samples are collected. The test data are collected 120 times per second, for each eye. Data are collected simultaneously from both eyes. Second, only when the stimulus is stationary and in the center of the screen are data collected and analyzed to minimize hippus volatility that occurs when targets are moving. Third, the testing procedure is standardized; that is, the luminance of the screen as well as stimuli timing and presentation are the same for each participant. Fourth, the resulting normative metrics explore the data from various angles, such as mean, standard deviation, range, variance, kurtosis, and confidence interval (CI; see Table 2). Using these metrics, an ", "individual’s results are measured against normative data. Normative data are based on a large sample size of 416 participants. Confidence intervals in the normative data show a very small range between the 95% CI upper and lower bounds. All these factors combined are considered in response to hippus and therefore allow the results of an individual’s data to be referenced in confidence to the pool of data reported while considering the hippus effect. ", "Furthermore, to ensure overall testing accuracy, each tester was trained on how to run each test with accuracy and consistency and was given 1 hour of dedicated training. This was concluded with a test in the form of a demonstration to an experienced tester, requiring a ‘‘passing’’ grade prior to testing any participants. ", "Data Analysis ", "Reliability ", "Test-retest reliability for IPD and PD was analyzed with intraclass correlation coefficients (ICCs) between trials with Cronbach’s alpha (CA) and the standard error of mean (SEM) for each ICC. Alpha level was set at P , 0.05 for all statistical tests. The ICC " ]

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[ null, "CRP) and by designing the test to meet with current standard measure of IPD and PD. Raw data for each test were collected as a whole number value; however, the analysis is reported as mean values carried out to two decimal points. ", "Results ", "Normative data for IPD is found in Table 1. In addition, Table 2 demonstrates the normative data for PD. Following CA, ICCs and associated SEM for test-to-test reliability (test 1 and test 2) are reported for IPD and PD. Observations for all variables demonstrated strong reliability. ", "Observations for IPD demonstrated perfect reliability with CA ¼ 1.00, which is well above the acceptable level of 0.70 and ICC ¼ 1. Calculated SEMs suggest the measures are capable of accurate assessment of IPD (test 1: SEM¼ 0.148; test 2: SEM¼ 0.440). Age had no effect on reliability for IPD. ", "Reliability PD ", "Cronbach’s alpha, ICC, and associated SEM for test-to-test reliability (test 1 and test 2) are reported in ", "Table 3. PD Reliability ", null, "ICC ¼ intraclass correlation coefficients; SEM ¼ standard error of the mean. * P , 0.001. CA = Cronbach’s Alpha; ", "indicates the relative reliability and is interpreted using the following criteria: ICC . 0.75 specifies excellent reliability and 0.40 , ICC . 0.74 represents fair to good reliability. ", "Validity ", "Convergent validity was investigated by calculating the bivariate correlation coefficient of the RightEye IPD/PD test and PL850 Pupilometer and the bivariate correlation coefficient of the RightEye IPD/ PD test and Essilor Digital CRP. Validity was also explored by examining the convergent findings within the analysis of variance test of each measure (RightEye IPD/PD test, PL850 Pupilometer, Essilor Digital ", "Figure 4. Bland-Altman plot comparing RightEye IPD/PD and PL850 Pupilometer. (Note: for all Bland-Altman plots, the solid line shows the mean difference, whereas the dashed line shows 95% limits of agreement). " ]

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[ null, "Figure 5. Bland-Altman plot comparing Righteye IPD/PD and Essilor Digital CRP. ", "Table 3. Observations for all variables demonstrated strong reliability. All CAs are above the acceptable level of 0.7, which is considered ideal (Tavakol and Dennick).30 Calculated SEMs represent an accurate assessment of PD. In addition, all ICCs were statistically significant at the P , 0.001 level. There was no effect of age on reliability for PD. ", "Validity IPD ", "Correlation analyses revealed high positive significant correlations between the RightEye IPD/PD test and PL850 Pupilometer (r ¼ 0.971, n ¼ 659, P , 0.001) and Essilor Digital CRP (r ¼ 0.985, n ¼ 659, P , 0.001). The Bland-Altman plots for IPD and PL850 (see Fig. 4) demonstrated no proportional bias and a mean difference of 0.407 (95% CI: 0.3026–0.5117). ", "Similarly, the Bland-Altman plots for IPD and Essilor Digital CRP demonstrate no proportional bias (see Fig. 5). ", "Two linear regression analyses were conducted: one to evaluate the proportional bias of RightEye IPD/PD test and PL850 and one to evaluate the proportional bias of RightEye IPD/PD test and the Essilor Digital CRP. Both regression analyses demonstrated a nonsignificant finding (R2¼ 0.056, F[1, 49] ", "¼ 0.105, P ¼ 0.748, and R2¼ 0.095; F[1, 49] ¼ 0.301, P ¼ 0.587, respectively). ", "Validity was further demonstrated in group differences analysis as all three variables (RightEye IPD/PD test, PL850 Pupilometer, and Essilor Digital CRP) produced equivalent results (see Table 4). In addition, validity was also established by design (see Methods section). ", "Validity PD ", "Correlation analyses for PD validity demonstrated high positive significant correlation between the RightEye IPD/PD left eye test and Rosenbaum left eye test (r ¼ 0.883, n ¼ 52, P , 0.001) and high significant correlation between the RightEye PD right eye test and Rosenbaum right eye test (r ¼ 0.851, n ¼ 52, P , 0.001). Rosenbaum method showed higher average PDs compared to the RightEye IPD/PD test (see Table 5); however, Bland-Altman plots (see Fig. 6 and Fig. 7) and regression analysis indicated no proportional bias for both left and right eye comparisons of the RightEye test and the Rosenbaum test (R2¼ 0.238, F[1, 49] ¼ 0.299, P ¼ 0.09, and R2¼ 0.110; F[1, 49] ¼ 0.607, P ¼ 0.439, respectively). ). In addition, validity was also established by design (see Methods section). " ]

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[ null, "Table 5. Descriptive Statistics for PD ", null, "correlation (CA) for IPD is 1.0 and for PD is 0.995– 0.997. ", "Although pupilometers have been examined and been found to be reliable,12 measures for IPD, consistent measurement of PD using various tools (lens systems, infrared light, and wavelength aberrometers) has been more difficult to demonstrate. In fact, Lawrence et al.,31 after testing PD in 200 healthy eyes, concluded that ‘‘due to the complex interaction among observer, pupillometry technique, and iris color, one cannot compare the four techniques to each other with the same observer, nor can one compare the two observers irrespective of the technique.’’ Past research has also found poor reliability in pupilometers due to examiner error such as incorrect positioning.5,13 The results of this study, however, indicate that the test is consistent over time given the same environmental conditions while ", "Table 4. Descriptive Statistics for IPD ", "RightEye Mean (SD) Sex Male 64.32 (1.50) Female 61.53 (2.66) PL850 Pupilometer Mean (SD) 63.00 (1.87) 60.41 (2.68) Essilor Digital CRP Mean (SD)P 65.00 (1.78) 61.05 (2.76) ", "Discussion ", "The purpose of this study was to determine the reliability of IPD and PD measures using an infrared eye tracker (SMI 12’’ 120 Hz) and central point stimuli (designed by RightEye, LLC). Results reveal the test-to-test reliability is strong for both IPD and PD. For all metrics, CAs are above the acceptable level of 0.7, which is considered ideal.30 ", "Past research by Obstfeld and Chou12 found consistent readings against nine of the leading pupilometers within the limits of clinically acceptable parameters (that is, mean differences of 2.3 mm and SD¼ 0.26 mm). Results from this study are at least in line with, if not stronger than, the pupilometers as the ", "Figure 6. Bland-Altman plot comparing RightEye IPD/PD left eye test and Rosenbaum left eye test. " ]

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[ null, "Figure 7. Bland-Altman plot comparing RightEye PD right eye test and Rosenbaum right eye test. ", "following the testing procedure outlined. There was also no effect of age on reliability for IPD or PD. Consistency in output is important but does not demonstrate accuracy. Therefore, our second objective was to determine if the RightEye IPD/PD test is accurate across all measures. ", "The RightEye IPD test compared to the PL850 Pupilometer and the Essilor Digital CRP determined IPD to be accurate and valid. Results revealed significant positive correlations (P , 0.001) when comparing output of the RightEye IPD results compared to both the PL850 Pupilometer and the Essilor Digital CRP, therefore suggesting that the RightEye IPD test is, at a minimum, as accurate as these other measures. Descriptive statistics (means and standard deviations) across all measures fall within a similar range, with the PL850 producing lower IPDs than the RightEye and Essilor Digital CRP tests. ", "The validity of the RightEye PD test compared to the RPVS for PD measures was also examined and resulted in a high positive correlation between the two tools (P , 0.001). Past research has found that the RPVS overestimated PD and may not be appropriate for evaluating PD for refractive surgery.16 In this ", "study, the RPVS also showed a higher average PD than the RightEye PD test. ", "Accurate and reliable measures of PD can be difficult for various reasons (hippus, eye color, luminance, and technique used). Nevertheless, it is important in modern ophthalmologic practice because of modern refractive surgery.32 Schmidt et al.,14 found statistically significant deviations in lens systems, infrared light, and wavelength aberrometers. Various infrared eye trackers have found that these eye trackers can over- and underestimate PD depending on eye position.18 When the eye is not positioned straight ahead, the pupil may appeared squashed, giving inaccurate readings. Therefore, the design of this experiment included stimuli that measure PD at a central point of fixation. Results revealed central PD measures ranged from 0.26 to 0.28 mm. These results are improved compared with past eye-tracking research,18 showing that central PD measures ranged from 0.3 to 1 mm. This may be due to the location of the stimuli when measuring PD with eye tracking. ", "The third objective of this study was to examine the data to establish normative references, for which individuals can measure themselves. Normative data " ]

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[ "are based on large sample size of 416 participants that were well matched in terms of gender (45% males and 55% females) across a wide range of age (18–73 years: M ¼ 42, SD ¼ 8.7) and ethnic backgrounds. These data are an adequate reference for comparison for people with normal vision development. ", "This experiment is not without limitations. Future studies should measure the RightEye PD test output against more sophisticated methods of measurement such as monocular autorefractors (e.g., Marco Nidek ARK-530A, Keeler PupilScan II, or NeurOptics PLR200). Future research should also examine the RightEye stimuli against other eye trackers (e.g., Tobii, SR Research and EyeTribe). ", "These results are limited to participants with normal visual function. Additional experimentation should consider those with refractive errors, nystagmus, and other vision-related disorders to determine the tests’ reliability. ", "A further exploration into various demographic factors such as ethnicity, gender, and age is needed. Past research has found differences across these variables that, with more specific analysis, would allow people to measure themselves against a more similar normative comparison. ", "Acknowledgments ", "Statement of Conflict of Interest: N.P. Murray and T. Bolte are independent of the company RightEye, LLC, with no conflicts of interest. All analysis and results are conducted by N.P. Murray. All data collection was conducted independently of RightEye by experienced vision specialists. M. Hulfalvay works for RightEye as a scientist, is blind to the analysis, and follows all ethical considerations during the scientific and experimental process. ", "Disclosure: N.P. Murray, None; M. Hunfalvay, None; T. Bolte, None ", "References ", "1. Rosenberg LB. The effect of interocular distance upon the operator performance using stereopic displays to perform virtual depth tasks. IEEE VRAIS Proc. 1993;93:27–32. 2. Filipovic T. Changes in the interpupillary distance (IPD) with ages and its effect on the near ", "convergence/distance (NC/D) ratio. Coll Antropol. 2003;27:723–727. 3. Jiang B, Ramamirtham R. The adaptive effect of narrowing the interocular separation on the AC/ A ratio. Vision Res. 2005;45:2704–2709. 4. Bosten JM, Goodbourn PT, Lawrance-Owen AJ, Bargary G, Hogg RE, Mollon JD. A population study of binocular function. Vision Res. 2015;110: 34–50. 5. Holland BJ, Siderov J. Repeatability of measurements of interpupillary distance. Opthalmic Physiol Opt. 1998;19:74–78. 6. Shafiee D, Jafari AR, Shafiee AA. Correlation between interpupillary distance and stereo acuity. Bull Environ Pharmacol Life Sci. 2014;3:26–33. 7. MacLachlan C., Howland HC. Normal values and standard deviations for pupil diameter and interpupillary distance in subjects aged 1 month to 19 years. Opthal Physiol Opt. 2002;22:175–182. 8. Howland HC, Howland B. A subjective method for the measurement of monochromatic aberrations of the eye. J Opt Soc Am. 1997;67:1508– 1518. 9. Oyster CW. The Human Eye: Structure and Function. Sunderland, MA: Sinauer Associates; 1999:103–105. 10. Dodgson N. Variation and extrema of human interpupillary distance. Proc Int Soc Opt Eng. 2004;5291:36–46. 11. Fesharaki H, Rezaei L, Farrahi F, Banihashem T, Jahanbkhshi A. Normal interpupillary distance values in an Iranian population. J Ophthalmic Vis Res. 2012;7:231–234. 12. Obstfeld H, Chou R. A study of the accuracy of corneal reflection pupillometers. Opthal. Physiol. Opt. 1998;18:527–531. 13. Schallenberg M, Bangre V, Steuhl K-P, Kremmer S, Selbach M. Comparison of Colvard, Procyon, and Neuroptics pupillometers for measuring pupil diameter under low ambient illumination. J Refractive Surgery. 2010;26:134–143. 14. Schmitz S, Krummenauer A, Henn S, Dick HB. Comparison of three different technologies for pupil diameter measurement. Graefe’s Arch Clin Exp Ophthalmol. 2003;241:472–477. 15. Loewenfeld IE. The Pupil: Anatomy Physiology, and Clinical Applications, 1st ed. Ames, IA: Iowa State University Press, v. 1; 1993: chapter 15. 16. Wachler BSB, Krueger MD. Agreement and repeatability of infrared pupillometry and the comparison method. Ophthalmology. 1999;106: 319–323. 17. Brown SM, Bradley JC. Comparison of 2 " ]

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[ "the dark-adapted pupil for measurement of diameter. J Cataract Refract Surg. 2011;37:660– 664. 18. Brisson J, Mainville M, Mailloux D, Beaulieu C, Serres J, Sirois S. Pupil diameter measurement errors as a function of gaze direction in corneal reflection eyetrackers. Behav Res. 2013;45:1322– 1331. 19. Evereklio˘glu C, Do˘ganay S, Er H, G¨und¨uz A. Distant and near interpupillary distance in 3448 ¨Ozal Tıp male and female subjects. Turgut Merkezi Dergisi. 1999;6,84–91. 20. Rio D, Woog K, Legras R. Effect of age, decentration, aberrations and pupil size on subjective image quality with concentric bifocal optics. Ophthalmic Physiol Opt. 2016;411–420. 21. Winn B, Whitaker D, Eilliot DB, Phillips NJ. Factors affecting light adapted pupil size in normal human subjects. Invest Ophthalmol Vis Sci. 1994;35:1132–1137. 22. Iyami E, Osuobeni E. Age, gender, corneal diameter, corneal curvature and central corneal thickness in Nigerians with normal intra ocular pressure. J Optom. 2012;5:87–97. 23. Wang D, He M, Wu L, et al. Dark-light change of iris parameters and related factors among American Caucasians, American Chinese, and mainland China. Curr Eye Res. 2012;37:599–605. 24. Kooiker MJG, Pel JJM, Verbunt HJM, de Wit GC, van Genderen MM, van der Steen J. Quantification of visual function assessment ", "using remote eye tracking in children: Validity and applicability. Acta Ophthalmol. 2016;94:599– 608. 25. Niehorster DC, Cornelissen THW, Holmqvist K, Hooge ITC, Hessels RS. What to expect from your remote eye-tracker when participants are unrestrained. Behav Res. 2017;1–15. 26. Renard D, Ferraro A, Lorenzini M-C et al. Orthoptic and video oculographic analyses in oculopharyngeal muscular dystrophy. Muscle Nerve. 2015;52:554–558. 27. Han SJ, Guo Y, Granger-Donetti B, Vicci VR, Alvarez TL. Quantification of heterophoria and phoria adaptation using automated objective system compared to clinical methods. Ophthalmic Physiol Opt. 2010;30:95–107. 28. Shtefanova OY, Yakushev AG. A quality criterion for visual tracking during nystagmus. Vestnik Moskovskogo Universiteta, Matematika. Mekhanika. 2008;63,63–65. 29. Holmqvist K, Nystrom M. Eye Tracking: A Comprehensive Guide to Methods and Measures. Oxford: Oxford University Press; 2011:131–134. 30. Tavakol M, Dennick R. Making sense of Cronbach’s alpha. Int J Med Educ. 2011;2:53–55. 31. Lawrence YH, Harvey MD, Scherer J, et al. Comparison of Rosenbaum pupillometry card using red and blue light Colvard and Iowa pupillometers. J Refract Surg. 2010;26:498–504. 32. Rosen ES. Quantify. J Cataract Refract Surg. 2002;28:203–204. " ]

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[ "Diagnostic yield of repeat sampling with immunoassay, real-time PCR, and toxigenic culture for the detection of toxigenic Clostridium difficile in an epidemic and a non-epidemic setting ", "J. van Prehn 1 & C. M. J. E. Vandenbroucke-Grauls 1 & Y. H. van Beurden 1 & R. van Houdt 1 & S. Vainio 1 & C. W. Ang 1 ", "Several multiple-step algorithms, with combinations of different diagnostic tests, have been proposed to achieve acceptable turn-around times and adequate sensitivity [2, 5–11]. Routinely ordering repeat testing for C. difficile is generally discouraged in a non-epidemic setting as it does not seem to increase diagnostic yield sufficiently [10–12]. It may also lead to more false-positive results as has been pointed out by a ", "rounds yielded 3 (9.1 %, −0.7 to 18.9), 3 (4.5 %, −0.5 to 9.6), 7 (8.4 %, 2.5 to 14.4), and 6 (6.5 %, 1.5 to 11.4) extra positives. In conclusion, repeat testing resulted in 4.5 % to 9.3 % extra positives. No significant difference between the settings studied could be demonstrated. Repeat sampling and multimodality testing may be chosen in an outbreak situation to detect all cases, effectively controlling nosocomial spread. ", "Introduction ", "Rapid diagnosis of Clostridium difficile-associated diarrhea (CDAD) is important for both therapeutic purposes and the timely application of adequate infection control measures. Several diagnostic tests for the detection of toxigenic C. difficile are available. Bacterial culture is an important modality as it yields isolates for (ribo-)typing, but it is hampered by the relatively long time interval before reporting results. Immunoassays are directed to either an enzyme carried by C. difficile (glutamate dehydrogenase) or toxins produced by C. difficile (TcdA and TcdB). These immunoassays are more rapid diagnostic tests, but it is well known that direct immunoassay testing of stool samples lacks adequate sensitivity for the detection of toxigenic C. difficile, with a sensitivity of 60– 70 % [1–3]. Real-time polymerase chain reaction (PCR)based diagnosis has proved to be highly sensitive and has become more widely available [1, 4]. ", "Abstract Current international guidelines lack definite conclusions regarding repeat stool sampling for the detection of toxigenic Clostridium difficile. We assessed the value of repeat sampling and compared the diagnostic yield in an epidemic to a non-epidemic setting. Consecutive fecal samples obtained during two time frames were analyzed using direct stool immunoassay toxin testing (enzyme immunoassay [EIA]), direct stool real-time PCR toxin gene testing, and toxigenic culture. Samples collected within 7 days of the initial sample were considered repeat tests. In the epidemic setting 989 patients were analyzed, and in the non-epidemic setting 1,015. In the epidemic setting 204 patients had two or more specimens included for analysis and in the non-epidemic setting 287 patients. In the epidemic setting 136 samples yielded a positive results, either by EIA or toxigenic culture; of these, 108 were positive according to EIA and 123 according to toxigenic culture. In the first test round 98 (90.7 %, 95 % CI 85.3 to 96.2), 114 (92.7 %, 88.1 to 97.3), and 126 (92.6 %, 88.3 to 97.0) positives were detected. Subsequent test rounds yielded 10 (9.3 %, 3.8 to 14.7), 9 (7.3 %, 2.7 to 11.9), and 10 (7.4 %, 3.0 to 11.7) extra positives. In the nonepidemic setting EIA, toxigenic culture and PCR detected 33, 66, and 83 positives. The three tests combined 93 detected positives. In the first test round 30 (90.9 %, 81.1 to 100.7), 63 (95.5 %, 90.4 to 110.5), 76 (91.6 %, 85.6 to 97.5), and 87 (93.5 %, 88.6 to 98.5) positives were detected. Subsequent test " ]

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[ "modelling study that assumes that test performance does not change during repeat testing [13]. The discouragement of routine repeat testing may lead to the false assumption that there is no value in repeat sampling at all. However, repeat testing seems beneficial in outbreak situations in which the prevalence is higher [14]. This has been underlined by the 2014 ESCMID guidelines, although the level of recommendation was graded only 3 out of 4 [11]. In the 2010 IDSA guidelines Bthe role of repeated stool during the same episode of illness^ is defined as a research gap. In the present study, our primary aim is to assess the value of repeat sampling for several widely used test modalities. Our secondary aim is to compare the diagnostic yield of repeat testing during a C. difficile hospital epidemic and compare this with a non-epidemic setting. ", "Materials and methods ", "Specimens ", "The results of stool testing for C. difficile during an epidemic and non-epidemic setting at our university hospital were analyzed. The results were prospectively entered into a database, which was retrospectively queried. Consecutive samples taken from January through December 2013 were included for the analysis of the epidemic setting. Consecutive samples taken from April 2014 through March 2015 were included for the non-epidemic analysis. Diagnostic tests were performed according to our institutional protocol: stool samples were tested directly with an immunoassay for the presence of toxins A and B, and were tested using toxigenic culture. All stool samples from the non-epidemic timeframe and a consecutive subset from the epidemic timeframe (from the end of November 2013 onward) were also tested directly with real time-PCR for toxin A and B genes. Tests that did not include all available modalities as described above were excluded from the analysis. ", "Direct toxin testing ", "Stool samples were tested for toxins A and B using the VIDAS CDAB enzyme-linked fluorescence assay (Biomérieux). Standardized samples of stool (200 μl) were added to 1 ml of diluent and centrifuged for 5 min at 12, 300 rpm. Subsequently, 300 μl of supernatant was added to the sample well of the CDAB kit. Based on the fluorescence, results were reported as positive (test value≥0.37), equivocal (≥0.13 to 0.37), and negative (<0.13). ", "Toxigenic culture for C. difficile ", "Stool samples were suspended in 95 % ethanol and incubated for 1 h at room temperature. A sample of the suspension was ", "then inoculated on selective CLO agar (cycloserine 100 μg/ml, cefoxitin 8 μg/ml, and amphotericin B 2 μg/ml; Biomérieux) and incubated for 3 days at 37 °C under anaerobic conditions. Suspect colonies were confirmed to be C. difficile by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry with the Vitek MS system (Biomérieux). In the epidemic setting positive toxigenic culture was defined as a positive direct stool toxin testing + cultured C. difficile or a cultured C. difficile isolate with positive toxin testing of the isolate. To this end, isolates were inoculated in a chopped-meat glucose broth [15]. After 1 and 2 days of incubation a sample of the broth was tested with the VIDAS CDAB immunoassay for the presence of toxins A and B. In the non-epidemic setting positive toxigenic culture was defined as a positive direct stool toxin gene assay + cultured C. difficile or a cultured C. difficile isolate with subsequent positive toxin gene testing. ", "Real-time PCR ", "A standardized amount of stool was dissolved in 1 ml S.T.A.R.-buffer (Roche Diagnostics) and kept at −80 °C for at least one hour. After 10 min at 100 °C, DNA was extracted using the MagNA-Pure96 platform (Roche Diagnostics). DNA was then amplified using a Real-Time PCR targeting the C. difficile toxin genes cdtA and cdtB, as previously described by de Boer et al. [16]. This PCR was performed using the LightCycler480 platform and software (Roche Diagnostics). ", "Analysis ", "All samples from a patient collected within 7 days of the first sample were considered to be repeat tests. Test results of samples collected after this 7-day period were not included in the patient level analysis. All patients were clinically suspected of CDAD and when a positive result was reported for either test modality, they were treated accordingly (cessation of antibiotic therapy where possible and/or metronidazole or vancomycin per os) and appropriate infection prevention measurements were taken. The diagnostic yield of extra test rounds was calculated using 95 % confidence intervals (asymptotic Wald method). ", "Results ", "Sample level ", "During the epidemic setting, 1,883 stool samples were taken, of which 11 were excluded because no culture result was available, and 4 because no direct immunoassay was available. After exclusion, there were 1,868 samples available for " ]

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[ "Tests were only considered to be repeat tests when samples of a patient were collected within 7 days of the first sample ", null, "epidemic timeframe [17]. In the epidemic timeframe there were 282 samples that tested positive with either immunoassay or toxigenic culture, 263 of which were toxigenic culture positive; in 19 samples toxin was demonstrated while C. difficile was not cultured. In the nonepidemic timeframe there were 185 samples that tested positive with either immunoassay, toxigenic culture, or PCR; 60 of these samples tested positive with immunoassay, 169 with PCR, and 143 with toxigenic culture. In ", null, "level analysis in a the epidemic timeframe and b the nonepidemic timeframe. Samples with a positive result are shown. In the epidemic timeframe there were 1,586 samples with both a negative direct enzyme immunoassay (EIA) and toxigenic culture. In the non-epidemic timeframe there were 1,523 samples with a negative direct EIA, negative direct polymerase chain reaction (PCR), and a negative toxigenic culture (8 PCR results that were not interpretable were regarded as negative) ", "analysis of the epidemic timeframe. During the non-epidemic setting 1,745 stool samples were taken, of which 37 were excluded: 3 had no direct PCR and direct immunoassay on stool available, 16 had no culture, 13 had no direct PCR on stool, and 5 had no direct immunoassay test. After exclusion, there were 1,708 samples available for analysis of the nonepidemic timeframe. The results of this analysis and the overlap of the positive test results are shown in a Venn diagram in Fig. 1a for the epidemic timeframe, and in Fig. 1b for the non", "Table 1 Number of patients included per test round for the epidemic and non-epidemic timeframe " ]

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[ "Table 2 Diagnostic yield of repeat testing in the epidemic setting ", null, "The number of positive patients detected by the different diagnostic modalities is shown with the percentage diagnostic yield per test round and 95 % confidence intervals EIA enzyme immunoassay ", "Table 3 Diagnostic yield of repeat polymerase chain reaction (PCR) in the epidemic setting ", "Discussion ", "In the present study we evaluated repeat C. difficile testing using several diagnostic modalities and found that repeat sampling resulted in 4.5 % to 9.3 % extra positives. We could not demonstrate a significant difference between the epidemic and non-epidemic settings studied. The largest increase in positive patients was found when we used all tests on the primary sample, compared with direct PCR only. Direct PCR testing with repeat samples yielded a few more positive patients. The same was true, to a lesser extent, when toxigenic culture was added to direct PCR. The highest number of positive patients will be detected with multiple modality testing and repeat testing. ", "To prevent bias caused by patient-to-patient transmission, we have limited the interval of repeat testing and only analyzed the first episode of test series per patient. As the Venn diagrams of the sample level analysis clearly illustrate, it is hard to define a true gold standard when all modalities used seem to miss some positives that are detected using other modalities; however, Fig. 1b illustrates that PCR testing will result in the highest detection rate of patients with a positive immunoassay, PCR or toxigenic culture. In clinical practice we initiated CDAD treatment and infection prevention measures if any of the tests were positive. It is of interest that of the 33 samples that only tested positive with PCR, several samples belonged to patients who tested positive with other modalities before or afterward, i.e., patients with emerging or regressing disease. This probably indicates that the PCR is indeed more sensitive than the other tests studied. In the ", "9 samples toxin was demonstrated using immunoassay, while C. difficile was not cultured. There were 33 stool samples in which toxin genes were demonstrated while no toxin was detected and no C. difficile was cultured. ", "Patients ", "In the epidemic setting, 989 patients were analyzed, and in the non-epidemic setting 1,015 patients were analyzed. The number of patients that were included per test round for each timeframe can be found in Table 1. In the epidemic situation, 136 patients tested positive with either toxin testing or toxigenic culture. In the non-epidemic setting a total of 93 patients tested positive with either toxin testing, toxigenic culture or toxin gene testing. The diagnostic yield of repeat testing in the epidemic situation ranged from 7.3 to 9.3 %, for detailed results see Table 2. Subset analysis of 137 patients tested with PCR, 30 of whom tested positive, indicated a diagnostic yield of 10 % of repeat PCR testing in the epidemic situation (Table 3). Repeat testing in the non-epidemic situation resulted in a diagnostic yield ranging from 4.5 % to 9.1 %, for detailed results see Table 4. The 95 % confidence intervals of the diagnostic yield of repeat testing showed overlapping results, indicating no significant difference between the epidemic and nonepidemic setting. ", null, "Analysis of a consecutive subset tested with PCR. The number of positive patients detected is shown with the percentage diagnostic yield per test round and 95 % confidence intervals " ]

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[ "Table 4 Diagnostic yield of repeat testing in the non-epidemic setting ", null, "The number of positive patients detected by the different diagnostic modalities is shown with the percentage diagnostic yield per test round and 95 % confidence intervals ", "present study, we have regarded equivocal EIA results as negative. Of the 63 samples with equivocal results in the nonepidemic setting, 47 were negative with both direct PCR and toxigenic culture, and 16 were positive with both direct PCR and toxigenic culture. If these equivocal results were regarded as positive, this would lead to an increase in concordance between EIA and PCR/toxigenic culture. However, this would also lead to an even larger increase in samples that were positive only according to EIA; these could be false-positives. ", "Our study has some limitations. In the epidemic setting, only a consecutive subset of the patients received a PCR test; however, this subset contains a considerable number of patients with a positive test. Furthermore, in the non-epidemic setting, PCR analysis was carried out on all samples included in the study (and no significant differences in diagnostic yield of repeat testing with any modality was demonstrated between the two settings). It could be argued that a multicenter study would be necessary to externally validate our results. However, our results are based on a commonly used and commercially available immunoassay, standardized regular bacterial culture techniques, and a previously described PCR method. ", "Our results agree with the outcome of the study by Debast et al., who found that repeat C. difficile toxin testing of stools within 1 week yielded 5 % of positive patients [14]. They concluded that repeat toxin testing of stools is of value for controlling outbreaks of C. difficile infection. From our own experience, we agree with this point of view. Other studies found a lower diagnostic yield from repeat testing [12, 18]. For example, in a study by Aichinger et al. it was concluded that repeat testing by enzyme immunoassay and PCR is of little value, as diagnostic gains of less than 2 % were calculated [12]. A more recent study by Green et al. found that only 11 out of 1,066 PCR tests repeated within 7 days (1 %) were positive [18]. When taking into account the costs of routinely ordering repeat testing and the low diagnostic yield, it seems inadvisable to routinely apply repeat testing in the nonepidemic setting [19]. ", "As pointed out in a paper by Peterson and Robicsek, there is a risk of more false-positives with repeat sampling, ", "assuming that test performance does not change with repeat sampling [13]. However, in clinical practice repeat testing is ordered, especially in patients with continuing clinical suspicion of CDAD, thereby altering the a priori chance of a positive test result, which affects test characteristics and subsequently diagnostic yield. Although we could not demonstrate a statistically significant difference in the diagnostic yield of repeat testing between the two settings, the absolute diagnostic yield in the epidemic setting will be higher by definition. Furthermore, in an outbreak situation it is paramount to have the highest sensitivity possible and to find every CDAD case. To this end, it might be better to accept more false-positives and apply repeat sampling and multimodality testing to increase sensitivity and effectively control nosocomial spread. ", "Acknowledgements The authors would like to thank Marije Bomers, MD, infectious disease specialist at VU University Medical Center, and Rosa van Mansfeld, MD, PhD, medical microbiologist at VU University Medical Center, for their cooperation. ", "Open Access This article is distributed under the terms of the Creative Comm ons Att ributi on 4 .0 Inte rnati onal Li cense (htt p: // creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. ", "References ", "1. Peterson LR, Manson RU, Paule SM, Hacek DM, Robicsek A, Thomson RB Jr, Kaul KL (2007) Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C. difficile-associated diarrhea. Clin Infect Dis 45:1152–1160 2. Shin BM, Kuak EY, Lee EJ, Songer JG (2009) Algorithm combining toxin immunoassay and stool culture for diagnosis of Clostridium difficile infection. J Clin Microbiol 47:2952–2956 3. Alcala L, Marin M, Madrid M, Dominguez-Garcia E, Catalan P, Pelaez MT, Sanchez-Somolinos M, Bouza E (2010) Comparison of ImmunoCard Toxins A&B and the new semiautomated Vidas " ]

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[ "Clostridium difficile Toxin A&B tests for diagnosis of C. difficile infection. J Clin Microbiol 48:1014–1015 4. Stamper PD, Alcabasa R, Aird D, Babiker W, Wehrlin J, Ikpeama I, Carroll KC (2009) Comparison of a commercial real-time PCR assay for tcdB detection to a cell culture cytotoxicity assay and toxigenic culture for direct detection of toxin-producing Clostridium difficile in clinical samples. J Clin Microbiol 47:373–378 5. Novak-Weekley SM, Marlowe EM, Miller JM, Cumpio J, Nomura JH, Vance PH, Weissfeld A (2010) Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol 48:889–893 6. Culbreath K, Ager E, Nemeyer RJ, Kerr A, Gilligan PH (2012) Evolution of testing algorithms at a university hospital for detection of Clostridium difficile infections. J Clin Microbiol 50:3073–3076 7. Reller ME, Lema CA, Perl TM, Cai M, Ross TL, Speck KA, Carroll KC (2007) Yield of stool culture with isolate toxin testing versus a twostep algorithm including stool toxin testing for detection of toxigenic Clostridium difficile. J Clin Microbiol 45:3601–3605 8. Swindells J, Brenwald N, Reading N, Oppenheim B (2010) Evaluation of diagnostic tests for clostridium difficile infection. J Clin Microbiol 48:606–608 9. Planche TD, Davies KA, Coen PG, Finney JM, Monahan IM, Morris KA, O’Connor L, Oakley SJ, Pope CF, Wren MW, Shetty NP, Crook DW, Wilcox MH (2013) Differences in outcome according to clostridium difficile testing method: a prospective multicentre diagnostic validation study of clostridium difficile infection. Lancet Infect Dis 13:936–945 10. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH, Society for Healthcare Epidemiology of America; Infectious Diseases Society of America (2010) Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 31:431–455 ", "11. Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ (2009) European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect 15:1053–1066 12. Aichinger E, Schleck CD, Harmsen WS, Nyre LM, Patel R (2008) Nonutility of repeat laboratory testing for detection of Clostridium difficile by use of PCR or enzyme immunoassay. J Clin Microbiol 46:3795–3797 13. Peterson LR, Robicsek A (2009) Does my patient have Clostridium difficile infection? Ann Intern Med 151:176–179 14. Debast SB, van Kregten E, Oskam KM, van den Berg T, Van den Berg RJ, Kuijper EJ (2008) Effect on diagnostic yield of repeated stool testing during outbreaks of Clostridium difficile-associated disease. Clin Microbiol Infect 14:622–624 15. Chang TW, Gorbach SL (1982) Rapid identification of clostridium difficile by toxin detection. J Clin Microbiol 15:465–467 16. De Boer RF, Wijma JJ, Schuurman T, Moedt J, Dijk-Alberts BG, Ott A, Kooistra-Smid AMD, van Duynhoven YTHP (2010) Evaluation of a rapid molecular screening approach for the detection of toxigenic Clostridium difficile in general and subsequent identification of the tcdC Δ117 mutation in human stools. J Microbiol Methods 83:59–65 17. Hulsen T, de Vlieg J, Alkema W (2008) BioVenn—a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics 9:488 18. Green DA, Stotler B, Jackman D, Whittier S, Della-Latta P (2014) Clinical characteristics of patients who tested positive for Clostridium difficile by repeat PCR. J Clin Microbiol 52:3853– 3855 19. Nistico JA, Hage JE, Schoch PE, Cunha BA (2012) Unnecesary repeat Clostridium difficile PCR testing in hospitalized adults with C. difficile-negative diarrhea. Eur J Clin Microbiol Infect Dis 32: 97–99 " ]

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[ "Congenital imprinting disorders: EUCID.net a network to decipher their aetiology and to improve the diagnostic and clinical care ", "Thomas Eggermann1,13*, Irène Netchine2,3,4, I Karen Temple5, Zeynep Tümer6, David Monk7, Deborah Mackay5, Karin Grønskov6, Andrea Riccio8,9, Agnès Linglart10,11 and Eamonn R Maher12 ", "Abstract ", "Imprinting disorders (IDs) are a group of eight rare but probably underdiagnosed congenital diseases affecting growth, development and metabolism. They are caused by similar molecular changes affecting regulation, dosage or the genomic sequence of imprinted genes. Each ID is characterised by specific clinical features, and, as each appeared to be associated with specific imprinting defects, they have been widely regarded as separate entities. However, they share clinical characteristics and can show overlapping molecular alterations. Nevertheless, IDs are usually studied separately despite their common underlying (epi)genetic aetiologies, and their basic pathogenesis and long-term clinical consequences remain largely unknown. Efforts to elucidate the aetiology of IDs are currently fragmented across Europe, and standardisation of diagnostic and clinical management is lacking. The new consortium EUCID.net (European network of congenital imprinting disorders) now aims to promote better clinical care and scientific investigation of imprinting disorders by establishing a concerted multidisciplinary alliance of clinicians, researchers, patients and families. By encompassing all IDs and establishing a wide ranging and collaborative network, EUCID.net brings together a wide variety of expertise and interests to engender new collaborations and initiatives. ", "Keywords: Imprinting disorders, Imprinted genes, Epimutation, Uniparental disomy, EUCID.net, Networking ", "Review ", "Introduction ", "Imprinting disorders (IDs) are a group of eight rare congenital diseases affecting growth, development and metabolism with a lifelong impact on patients’ quality of life. They are caused by changes in gene regulation (‘epigenetic mutation’), gene dosage and - rarely - in gene or genomic sequences (‘genetic mutation’) (Figure 1). The term genomic imprinting describes the expression of specific genes in a parent-of-origin-specific manner - that is, they are expressed only from the maternal or from the paternal gene copy, but not biparentally (for review: [1]). The underlying epigenetic basis does not involve the DNA sequence itself, but regulatory mechanisms that ensure ", "the transmission of specific gene expression patterns from one cell generation to another, ensuring the maintenance of cellular identity. ", "So far, more than 60 human genes have been shown to be imprinted, but there are probably many more (for review: [2]). The normal imprinting marks are inherited from the parental gametes and are then maintained in the somatic cells of an individual. Their programming is subject to an imprinting cycle during life which leads to a reprogramming at each generation (for review: [3]): In early development, methylation of the mammalian genome is comprehensively remodelled, but imprinting marks are exempt from developmental reprogramming; instead, they are erased in the germ line and re-established according to the sex of the contributing parent for the next generation. Many genes regulated by genomic imprinting are found in clusters, that is, imprinted loci often comprise multiple genes under coordinated control. At the molecular level, the expression of genes within imprinted regions " ]

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[ null, "Figure 1 The four molecular mechanisms of IDs, resulting in a disturbed expression of imprinted genes. ", "is influenced by specific patterns of DNA methylation, by changes in chromatin structure and by post-translational histone modifications, collectively designated as epigenetic regulation (for review: [4,5]). ", "The epigenetic machinery is extremely complex and results in a unique transcriptional activity of different cells with identical DNA sequences. Indeed, this carefully orchestrated interplay is prone to various disturbances resulting in distinct pathological courses, for example, malignant tumours or - in the case of parentally imprinted genes - IDs. In IDs, the regulation of imprinted genes can be disturbed by four different molecular alterations: genomic imbalances (duplications/deletions), uniparental disomy (UPD; the inheritance of both homologos of a chromosomal pair from only one parent), epimutations (disturbed methylation) or point mutations in an imprinted gene. Whereas in the majority of ID patients, only the disease-specific loci are affected, an increasing number of ID patients are reported showing a disturbed methylation at multiple differentially methylated regions (DMRs), the so-called multilocus imprinting disturbances (MLID) (see below). The extreme examples of unbalanced imprinting patterns are genome-wide UPDs, that is, the whole genome is inherited only from the father or from the mother. ", "In both cases, the resulting conception is not viable. However, mosaic genome-wide UPD has been reported to be compatible with life (for review: [6]). ", "The known imprinting disorders ", "Most patients with one of the currently established IDs are diagnosed in early childhood. In contrast, the diagnosis in the prenatal workup or puberty or adulthood is often hampered because the clinical spectrum is broad, and some features are subtle, overlapping and transient. As a result, some IDs are probably mis- and underdiagnosed. ", "Each ID is characterised by specific clinical features, and as they appeared to be associated with specific imprinting defects, they have been regarded as separate entities. Indeed, the majority of IDs have some shared clinical characteristics (Table 1), that is: ", "– prenatal and/or postnatal growth retardation or prenatal and postnatal overgrowth; – hypo- or hyperglycemia; – abnormal feeding behaviour in early childhood and later; and – behavioural difficulties in childhood. " ]

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[ "Table 1 Overview on the clinical and molecular characteristics of the currently known eight IDslocalization ", null, "As listed in the second column, for several IDs, different names have been proposed. To reach a consensus on a common nomenclature of IDs, EUCID.net has decided to use the disorders names listed on the left (see www.imprinting-disorders.eu). IUGR, intrauterine growth retardation; PNGR, postnatal growth retardation. aChromosomes. bCase [27] carries both upd(7)mat and an TS14 epimutations. " ]

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[ "Transient neonatal diabetes mellitus ", "Transient neonatal diabetes mellitus (TNDM) is a rare disease, characterised as its name implies by transient hyperglycaemia. In addition, IUGR, macroglossia and abdominal wall defects are common. Insulin therapy is required for an average of 3 months; afterwards, the diabetes resolves, but later in life, the majority of TNDM patients develop type 2 diabetes. TNDM is associated with an overexpression of PLAGL1/ZAC in 6q24, a maternally imprinted gene. It encodes a zinc-finger protein which binds DNA and hence influences the expression of other genes (for review: [7,8]). ", "Silver-Russell syndrome ", "Silver-Russell syndrome (SRS) is mainly characterised by prenatal and postnatal growth restriction with relative macrocephaly at birth, severe feeding difficulties during early childhood and typical facial gestalt and, in many cases, asymmetry. The genetic basis of SRS is heterogeneous. In approximately 10% of SRS patients, a maternal UPD for chromosome 7 [upd(7)mat] can be found (for review: [9,10]). More than 40% of SRS patients show a hypomethylation of the ICR1 DMR in the imprinted region 11p15. In single cases, genomic alterations in 11p15 chromosomal region have been reported (for example, maternal duplications). Additionally, numerous (submicroscopic) disturbances of other chromosomes than 7 and 11 have been described in SRS patients; thus, screening for cryptic genomic imbalances is indicated after exclusion of upd(7)mat and 11p15 epimutations [11,12]. Furthermore, there is an overlap with Temple syndrome (upd(14)mat). The genes causing the SRS phenotype on chromosomes 7 and 11 are currently unknown, but a role of IGF2 and CDKN1C in 11p15 has been suggested. ", "Beckwith-Wiedemann syndrome ", "Beckwith-Wiedemann syndrome (BWS) was initially called EMG syndrome from its three main features of exomphalos, macroglossia and (neonatal) gigantism. In 5% to 7% of children, embryonal tumours (most commonly Wilms tumour) are diagnosed. The clinical diagnosis of BWS is often difficult due to its variable presentation and the phenotypic overlap with other overgrowth syndromes (for review: [13,14]). In nearly 70% of BWS patients, an altered expression or mutations of several loci in 11p15 can be observed (including the ICR1 and ICR2 DMRs). ICR2 hypomethylation account for about 50% of the cases, upd(11p15)pat is the second most frequent molecular aberration, while ICR1 hypermethylation is less frequent (2% to 7%). Most BWS cases are sporadic, but familial inheritance is observed in 15% of all cases. Microdeletions/duplications or point mutations at the ICRs are usually found in familial BWS with aberrant ", "11p15 methylation, while CDKN1C mutations are frequent in familial cases with normal 11p15 methylation [15,16]. These BWS pedigrees resemble that of an autosomal dominant inheritance but with incomplete penetrance depending on the sex of the inheriting parent. A genotype/epigenotype-phenotype correlation has recently been established for BWS [17]: hemihypertrophy is strongly associated with upd(11)pat, exomphalos with ICR2 hypomethylation and CDKN1C mutations, and, most importantly, the risk of Wilms tumour is significantly higher in ICR1 hypermethylation and upd(11)pat than in the other molecular subgroups. In BWS, the determination of the molecular subtype is therefore important for an individual prognosis and therapy. Nevertheless, the phenotypic transitions are fluid, and testing for all molecular subtypes should be offered in patients with BWS features. ", "Temple syndrome (TS14) [upd(14)mat]) and Kagami-Ogata syndrome (KOS14) [upd(14)pat] ", "TS14 (upd(14)mat and WGS (upd(14)pat) were described in 1991 by Temple et al. and Wang et al. [18,19], respectively. However, the frequencies of both syndromes are currently unknown. Both IDs were first detected in patients carrying balanced Robertsonian translocations. Considering the most important formation mechanism of UPD via trisomy rescue, this observation was consequent because Robertsonian translocations are prone to trisomic offspring. More recently, several cases have been described with microdeletions affecting 14q32 or with isolated methylation anomalies affecting the imprinting control region [20,21]. ", "Among other clinical signs, TS14 is characterised by prenatal and postnatal growth retardation, muscular hypotonia, feeding difficulties in early childhood, truncal obesity and early onset of puberty. TS14 patients show clinical features overlapping with PWS and SRS, and thus, screening for chromosome 14q32 should be performed in patients with PWS- and SRS-like phenotypes after exclusion of the specific (epi)mutations. ", "KOS14 is associated with polyhydramnios, a characteristic small, bell-shaped thorax, abdominal wall defects and a severe developmental delay. Many patients have been reported to die in utero or in the first months of life, but exceptions exist. ", "For both syndromes, the role of an altered RTL1 and DLK1 expression has been suggested [21]. ", "Angelman and Prader-Willi syndromes ", "Both Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are caused by (epi)mutations in 15q11-q13. The lack of the paternal contribution of this region results in PWS, while lack of the maternal contribution leads to AS. Both AS and PWS patients are mentally retarded, but the " ]

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[ "remaining clinical signs are different. PWS is clinically characterised by neonatal hypotonia and failure to thrive in infancy, with subsequent development of hyperphagia and obesity (for review: [22]). Approximately 70% of individuals with PWS have an interstitial deletion of the paternal 15q11-q13 allele, 20% to 30% have maternal UPD of 15q11-q13 while <1% have an imprinting defect (either primary or secondary). As mentioned before, analysis for TS14 should be considered in PWS patients without chromosome 15 disturbances. ", "AS patients exhibit microcephaly, ataxia, seizures, absence of speech and sleep disorder (for review: [23]). Deletion of the maternal copy of 15q11-q13 is observed in approximately 70% of individuals with AS, paternal UPD in 7% to 10%, while 3% have an imprinting defect (either primary or secondary). Around 10% have mutations in UBE3A. ", "Due to the high percentage of microdeletions in 15q11q13 in both syndromes, AS and PWS also belong to the so-called microdeletion syndromes, a group of congenital disorders caused by a chromosomal deletion spanning several genes but too small to be detected by conventional cytogenetic. ", "Pseudohypoparathyroidism ", "Pseudohypoparathyroidism (PHP) is a group of disorders united by parathyroid hormone (PTH) resistance in the kidney, that is, pseudohypoparathyroidism. Most cases of PHP belong to the type 1, that is, are caused by genetic or epigenetic alterations at the imprinted GNAS locus. PHP1A comprises patients affected with resistance to PTH and thyroid stimulating hormone (TSH) and features of obesity and Albright’s hereditary osteodystrophy including short stature, brachydactyly, ectopic ossifications and mental retardation. PHP1A is due to loss of function mutations in the maternal allele of the GNAS gene. Paternal GNAS mutations are associated with AHO, no hormonal resistance and no obesity. In contrast, the phenotype of most PHP1B patients is limited to renal PTH resistance and in some cases, mild TSH resistance. Few patients with PHP1B display some features of Albright’s hereditary osteodystrophy. Patients with PHP1B share a loss of methylation at the A/B DMR of GNAS, likely leading to the downregulated expression of the GNAS-Gsa transcript in imprinted tissues. Some patients carry additional epigenomic changes along the GNAS locus. About 20% of PHP1B are inherited and due to deletions of GNAS imprinting control regions. The remaining 80% are sporadic. A small subset is due to paternal UPD of chromosome 20q, yet the vast majority are still of unknown cause. While obesity and short stature are long known features of PHP1A, it became only recently apparent that growth and metabolism are affected in both paternal and maternal epi/genetic alterations of the GNAS locus (for review: [24,25]). ", "Molecular alterations in IDs ", "In nearly all known IDs, the same classes of molecular changes are detectable. Broadly, the several mechanisms have an underlying genetic lesion, but a considerable number have no identifiable genetic cause, and are reproductive, stochastic or epigenetic in origin (Figure 1). ", "The genetic lesions include: ", "a) chromosomal deletions, duplications and rearrangements; b) intragenic mutations in imprinted genes. ", "In familial cases of these genetically caused IDs, parent of origin dependence of expression results in apparent nonMendelian inheritance. ", "The non-genetic causes consist of: ", "c) UPD (that is, the inheritance of both chromosomal homologos from the same parent); d) epimutations (that is, aberrant methylation without alteration of the genomic DNA sequence). ", "It is noteworthy that non-genetic aberrations may occur post-zygotically, resulting in a mosaic distribution. Mosaicism can obscure genotype-phenotype correlation, and is also associated with somatic asymmetry, and discordant monozygotic twinning. ", "For genetic counselling of ID families, the knowledge of the nature of the mutation or epimutation subtype is essential to delineate exact risk figures. Whereas the recurrence risk is generally low in the case of epimutations and UPD, patients/carriers with submicroscopic deletions or duplications might have a 50% risk of conceiving a child with an ID, depending on the sex of the contributing patient. However, in each case, genetic professionals are advised to continually update their knowledge for each disease. ", "Each of the currently known IDs was initially reported to be associated with molecular alterations at specific chromosomal loci. They have therefore been regarded as separate entities, but - as mentioned before - with the growing data on IDs, it becomes apparent that they share both genetic properties and clinical features. This can cause uncertainty determining which molecular tests to perform and with what priority, particularly for patients with growth restriction. Moreover, the clinical overlap between the different IDs is reflected on molecular level by the identification of similar multilocus methylation defects in different phenotypes. In particular, in growth retarded patients, it is sometimes difficult to decide which ID-specific test should be applied. ", "Multilocus imprinting disturbances, a common finding in IDs ", "The correlation between aberrations at specific imprinted genes and distinct congenital disorders was generally accepted for nearly 20 years, but there are growing numbers " ]

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[ "of reports on patients with generally disturbed imprinting patterns (MLID) (Table 1) (for review: [26]). These patients often exhibit a specific ID phenotype, for example, BWS, but molecular testing reveals that aberrant methylation does not affect only the disease-specific imprinted loci (for example, 11p15 in BWS) but also other imprinted regions. Remarkably, patients with opposite phenotypes like BWS (overgrowth) and SRS (growth retardation) can share some aberrant methylation patterns in lymphocytes (lymphocyte DNA is the most frequently and often the only analysed tissue), and to add a layer of complexity, epigenotype anomalies can vary for the same individual depending on the studied tissue. This has been so far investigated in SRS patients with 11p15 ICR1 LOM identified initially in leukocytes. Another example is the phenotype of an upd (7q)mat carrier with hypomethylation in 14q32 who was initially diagnosed as SRS (typical for upd(7q)mat but then exhibited a phenotype suggestive for TS14 [27]. ", "In summary, the clinical picture in patients with methylation aberrations affecting more than one imprinted locus can be different from that of patients with single epimutations, but is not necessarily so. As a result, both patients with typical ID phenotypes as well as those with unusual clinical features should be tested for MLID. ", "Two genetic mechanisms causing aberrant methylation at imprinted loci have been identified: cis- and trans-acting alterations. Cis-acting alterations affect DNA sequences which are physically localised adjacent to a structural gene or its control regions and interact with them. Examples for cis-acting mutations are rare deletions of CTCF-binding sites and mutations affecting the OCT- and SOX-binding elements in 11p15 which mediate the regulation of ICR1: such mutations affect up to 20% of BWS patients with 11p15 ICR1 GOM [28], but the BWS phenotype is expressed only if the mutation affects the maternal chromosome 11 [29,30]. Trans-acting factors also influence the expression of genes, but they act by intermediary diffusible molecules (proteins, RNAs). Their genes can be localised on the same chromosome as the target gene or elsewhere in the genome. Several trans-acting factors have been postulated to cause MLID (for review: [26]), and indeed, DNA mutations in factors involved in the imprinting cycle have been reported [31-33]. ", "In addition to these monogenic causes of aberrant imprinting, the identification of patients with MLID corroborates the hypothesis of an ‘imprinted gene network’, that is, a network of interacting imprinted genes and regions [34]. By this network, the disturbance of one member alters the regular expression of the others. ", "The COST Action BM1208: EUCID.net - a network of European groups working in the field of IDs ", "Despite their common underlying (epi)genetic aetiologies, IDs are usually studied separately by small groups working ", "in isolation, and the basic pathogenesis and long-term clinical consequences of IDs remain largely unknown. Efforts to elucidate the aetiology of IDs are currently fragmented across Europe, and standardisation of diagnostic and clinical management is lacking. ", "To overcome this fragmentation and to achieve a consensus in diagnostic and treatment of IDs, European groups working on IDs and epigenetic regulation have established a network, called EUCID.net (European network for human congenital imprinting disorders; www.imprinting-disorders. eu), which, for the first time, draws together researchers of all eight known human IDs in an interdisciplinary activity, working to advance understanding of the pathophysiology with the major aim of translating this knowledge to improvement of diagnostic and clinical management for the benefit of the patients and their families. The Action will harmonise a common system for clinical and molecular classification as well as nomenclature of IDs, develop guidelines for treatment through consensus, create standard operating procedures (SOPs) for diagnosis based on best current practice, coordinate databases held in different countries to make them compatible and useful as a springboard for collective research initiatives, identify new imprinting disorders through collaborative effort, educate researchers and stimulate translational exchange. These networking activities have become possible with funding of COST, the European Cooperation in Science and Technology, (COST Action BM1208). ", "Objectives of EUCID.net ", "The objectives of the network will be realised in five working groups (WGs) described below. The activities will run in three interdependent directions: (a) Clinical experts are undertaking the challenging task of standardisation and harmonisation of clinical phenotyping and medical management of IDs, providing guidelines for IDs’ clinical assessment and management across Europe. (b) Experts in molecular diagnosis are undertaking the standardisation of molecular diagnosis of IDs and development of consistent reproducible molecular testing. (c) A coordinated European infrastructure of data sharing (clinical and molecular data) and samples for genetic and epigenetic study of IDs will be created (with the possibility to link clinical, genetic and epigenetic data). This will be an important step towards improving the standard of care for IDs in Europe and uncovering the genetic/epigenetic bases of the disorders. ", "WG1 - European clinical integration ", "By European wide cooperation and coordination, this WG will gather Europe-wide experience in the clinical and metabolic characteristics and management practices of ID patients to provide a comprehensive clinical review of IDs. This will enable the development of standardised " ]

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[ "recording of phenotypes across centres and the development of a disease classification enabling future improvements in diagnosis. We will also strive for a current consensus on clinical management guidelines on which to build as new developments emerge. With the publication of disease-specific clinical utility cards, the first step has been undertaken [35-40]. ", "WG2 - molecular biology ", "This multidisciplinary WG will unify recording of samples to create a virtual biobank for IDs across Europe, creating pan-European resources for the study of the (epi)genetic basis of IDs. The heterogeneity and complexity of IDs demands the availability of large patient cohorts which has not been available until now. Furthermore, this WG will attempt to unify the types of the biological material obtained from affected families (DNA, RNA, transformation of lymphocytes). This will allow the identification of factors commonly involved in the aetiology of IDs. This WG will focus on activities aiming on the identification of new genes, cis-acting control elements and epigenetic trans-acting factors associated with and/or causing IDs as a prerequisite for an understanding of pathophysiological mechanisms. Unravelling the cross talk between known and new ID genes can place these disorders in an (epi)genomic perspective. This WG will coordinate genomic, epigenomic, proteomic and transcriptomic studies by high-throughput assays. By data exchange, these new findings and techniques will be implemented in clinical and diagnostic application. ", "WG3 - molecular diagnostics ", "WG3 will discuss important technical aspects related to molecular diagnosis of IDs, aiming to provide a harmonised testing algorithm for IDs. The partners in WG3 will implement innovative diagnostic algorithms by improvement of existing ID-specific tests and by development of new tests for specific IDs. The diagnostic utility of these techniques will be validated, and standardised algorithms will be progressively incorporated into diagnostic regimes through collective experience. Reference panels and quality control measures will be established in cooperation with the European Molecular Quality Network (EMQN). It is expected that most European experts in the field of IDs are going to participate in this effort and they will collaborate with experts around the world, thus turning this COST Action into a global initiative. ", "WG4 - capacity building ", "Being the springboard for new research ideas, this WG will use the combined experiences of COST members to initiate new directions and projects in ID research responding to research calls through the preparation and submission of grant proposals to European and ", "international funding agencies. Furthermore, networking activities and short-term scientific missions will be organised to strengthen the interdisciplinary and transnational activities. ", "WG5 - dissemination ", "This WG will design and coordinate outreach meetings with patient groups and dissemination activities. It will receive input from the other WGs and channel their scientific efforts into public dissemination. The publication of new disease classification systems and clinical guidelines, together with coordinated diagnostics, will represent a major objective for delivering individualized therapeutic management. This WG will promulgate the results, guidelines and clinical classifications to physicians, scientists and patients’ organisations. WG5 will have close links with national patients’ organisations. ", "Organisation ", "At the beginning in May 2013, 25 groups from 11 European countries have been part of EUCID.net, including academic groups, SMEs and patients’ organisations. Until July 2014, additional groups have joined the network, and it currently includes 45 groups from 22 European countries. Furthermore, there are close links and exchanges with experts from Australia, Canada, Japan, South America and the USA. ", "Based on the COST rules, the EUCID.net includes the following partcipants (Figure 2): A Chair and a ViceChair, both elected, who preside over the management committee (MC). The MC coordinates the key issues of the Action. It consists of two representatives per participating country, including the Coordinator and Co-Coordinator of each WG. It is responsible for the allocation of funds and oversees for the overall strategy of the network. The MC manages operations of the WGs, the programme of international symposia, as well as training and exchange programmes. The MC fosters the exchange of scientific knowledge and active collaborators. Due to its smaller size, the steering committee (SC), consisting of the WG co/ coordinators, represents a more flexible instrument that allows the close monitoring of the progress of the Action and acts as a link between the WGs and the different groups. Under the directions of the MC, the SC is furthermore responsible for the interaction with existing platforms in Europe and across the world and relevant stakeholders (for example, IRDiRC, EURORDIS, Orphanet, EMQN, EUCERD). Each of the five WGs is chaired by a WG leader (Coordinator) and a co-leader who have been elected by the MC during the kick-off meeting. Leader and co-leader are responsible for the coordination, organisation and supervision of the WG’s meetings. Each WG is constituted by different teams, but the teams can be involved in different WGs. All members of each WG will meet once a year " ]

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[ null, "Figure 2 Structure and activities of the EUCID.net/COST BM1208, all aiming on networking of researchers, clinicians, SMEs and patients organisation working in the field of IDs. ", "to establish the guidelines and SOPs as well as to exchange scientific knowledge and data. The investigators of each WG communicate through regular conference calls and web-based interfaces. All five WGs are interrelated and interact through the SC. WG 1 is closely related to WG 2 and 3, establishing tools and guidelines for phenotype characterization. In turn, WG 2 and 3 are connected to deciphering the molecular basis of IDs and to translate the achieved knowledge into diagnostic application. Furthermore, they contribute to the ID classification and development of clinical guidelines in WG 1. All efforts from WG1 3 support and stimulate the activities in WG 4 to initiate new directions and projects. WG1 4 support WG 5 in the promulgation of the data and achieved knowledge, inter alia by implementation of WG specific information on the website in a password protected area. ", "High priority is given to Early Stage Researchers (ESRs) and Short-Term Scientific Missions (STSMs) for maximizing the exchange of experience among the participants as exchanging ideas and knowledge across borders ", "will lead to more successful projects. The ID training school is a further central instrument to pursue these aims. ", "Conclusions ", "Imprinting disorders are underdiagnosed, and currently available diagnostic and management protocols are suboptimal. Improvements in the diagnosis and management of rare diseases are greatly facilitated by international collaboration. EUCID.net aims to promote better clinical care and scientific investigation of imprinting disorders by establishing a concerted multidisciplinary alliance of clinicians, researchers, patients and families. By encompassing all IDs and establishing a wide ranging, open and collaborative network, EUCID will bring together a wide variety of expertise and interests to engender new collaborations and initiatives. It is very much hoped that epigeneticists with an interest in imprinting disorders will wish to participate in EUCID.net (contact: teggermann@ukaachen.de). " ]

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[ "The authors declare that they have no competing interests. ", "Authors’ contributions ", "TE and ERM prepared the draft. All authors approved the content and contributed their expertise in the different fields of imprinting disorders, that is, TE, DM and IN in the field of Silver-Russell syndrome, ZET and KG for the chromosome 15 disorders, AR, IN and ERM for the Beckwith-Wiedemann syndrome, IKT and DJM for the chromosome 14 syndromes and TNDM, and AL for the PHP. All authors read and approved the final manuscript. ", "Acknowledgements ", "All authors are members of the EUCID.net network, funded by the COST (BM1208). ", "Author details ", "1Department of Human Genetics, RWTH Aachen, Aachen 52074, Germany. 2INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France. 3UMR_S 938, CDR Saint-Antoine, UPMC Univ Paris 06, Sorbonne Universites, Paris F-75012, France. 4Pediatric Endocrinology, 3APHP, Armand Trousseau Hospital, Paris 75012, France. 5Human Genetics and Genomic Medicine, Faculty of Medicine University of Southampton, Wessex Clinical Genetics Service, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK. 6Clinical Genetic Clinic, Kennedy Center, Rigshospitalet, Copenhagen University Hospital, Glostrup 2600, Denmark. 7Imprinting and Cancer Group, Cancer Epigenetic and Biology Program (PEBC), Institut d’Investigació Biomedica de Bellvitge (IDIBELL), Hospital Duran i Reynals, 08907 Barcelona, Spain. 8DiSTABiF, Seconda Università degli Studi di Napoli, 81100 Caserta, Italy. 9Institute of Genetics and Biophysics—ABT, CNR, Napoli, Italy. 10Endocrinology and Diabetology for Children and Reference Center for Rare Disorders of Calcium and Phosphorus Metabolism, Bicêtre Paris Sud, APHP, Le Kremlin-Bicêtre 94276Paris, , France. 11INSERM U986, INSERM, Le Kremlin-Bicêtre, 94276 Paris, France. 12Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, UK. 13Department of Human Genetics, University Hospital, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. ", "Received: 12 September 2014 Accepted: 26 January 2015 ", "Nat Rev Genet. 2001;2:21–32. Horsthemke B. Mechanisms of imprint dysregulation. Am J Med Genet C. 2010;154C:321–8. Demars J, Gicquel C. Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith-Wiedemann and Silver-Russell syndromes. Clin Genet. 2012;81:350–61. Delaval K, Wagschal A, Feil R. Epigenetic deregulation of imprinting in congenital diseases of aberrant growth. Bioessays. 2006;28:453–9. Kacem S, Feil R. Chromatin mechanisms in genomic imprinting. Mamm Genome. 2009;20:544–56. Kalish JM, Conlin LK, Bhatti TR, Dubbs HA, Harris MC, Izumi K, et al. Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. Am J Med Genet A. 2013;161:1929–39. Temple IK, Gardner RJ, Robinson DO, Kibirige MS, Ferguson AW, Baum JD, et al. Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23. Hum Mol Genet. 1996;5:1117–21. Temple IK, Shield JP. 6q24 transient neonatal diabetes. Rev Endocr Metab Disord. 2010;11:199–204. Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, et al. 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab. 2007;92:3148–54. 10. Abu-Amero S, Monk D, Frost J, Preece M, Stanier P, Moore GE. The genetic aetiology of Silver-Russell syndrome. J Med Genet. 2008;45:193–9. 11. Bruce S, Hannula-Jouppi K, Puoskari M, Fransson I, Simola KO, Lipsanen-Nyman M, et al. Submicroscopic genomic alterations in Silver-Russell syndrome and ", "growth retardation with Silver-Russell features. J Pediatr. 2012;161:933–42. 13. Cooper WN, Luharia A, Evans GA, Raza H, Haire AC, Grundy R, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2005;13:1025–32. 14. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J 15. Med Genet. 2010;154C:343–54. Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet. 2004;36:958–60. 16. Demars J, Shmela ME, Rossignol S, Okabe J, Netchine I, Azzi S, et al. Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders. Hum Mol Genet. 2010;19:803–14. Ibrahim A, Kirby G, Hardy C, Dias RP, Tee L, Lim D, et al. Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clin Epigenetics. 2014;6:11. Temple IK, Cockwell A, Hassold T, Pettay D, Jacobs P. Maternal uniparental disomy for chromosome 14. J Med Genet. 1991;28:511–4. 17. 18. 19. Wang JC, Passage MB, Yen PH, Shapiro LJ, Mohandas TK. Uniparental 20. 21. heterodisomy for chromosome 14 in a phenotypically abnormal familial balanced 13/14 Robertsonian translocation carrier. Am J Hum Genet. 1991;48:1069–74. Temple IK, Shrubb V, Lever M, Bullman H, Mackay DJ. Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14. J Med Genet. 2007;44:637–40. Kagami M, Sekita Y, Nishimura G, Irie M, Kato F, Okada M, et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet. 2008;40:237–42. 22. Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. 2004;15:12–20. 23. Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, 24. 25. 26. et al. Angelman 2005: updated consensus for diagnostic criteria. Am J Med Genet. 2005;2006(140A):413–8. Kelsey G. Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus. Am J Med Genet. 2010;154C:377–86. Linglart A, Maupetit-Méhouas S, Silve C. GNAS-related loss-of-function disorders and the role of imprinting. Horm Res Paediatr. 2013;29:119–29. Eggermann T, Heilsberg AK, Bens S, Siebert R, Beygo J, Buiting K, et al. Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing. J Mol Med. 2014;92:769–77. 27. Begemann M, Spengler S, Kordaß U, Schröder C, Eggermann T. Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation. Am J Med Genet A. 2012;158A:423–8. 28. Abi Habib W, Azzi S, Brioude F, Steunou V, Thibaud N, Neves CD, et al. Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome. Hum Mol Genet. 2014;23:5763–73. 29. Beygo J, Citro V, Sparago A, De Crescenzo A, Cerrato F, Heitmann M, et al. The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites. Hum Mol Genet. 2013;22:544–57. 30. Poole RL, Leith DJ, Docherty LE, Shmela ME, Gicquel C, Splitt M, et al. Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1. Eur J Hum Genet. 2012;20:240–3. 31. Meyer E, Lim D, Pasha S, Tee LJ, Rahman F, Yates JR, et al. Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome). PLoS Genet. 2009;5:e1000423. 32. Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet. 2008;40:949–51. 33. Murdoch S, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, et al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. 2006;38:300–2. 34. Varrault A, Gueydan C, Bellmann A, Houssami S, Aknin C, Severac D, et al. Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell. 2006;11:711–22. " ]

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[ "Eggermann T, Buiting K, Temple IK. Clinical utility gene card for: Silver-Russell syndrome. Eur J Hum Genet. 2011;19(3). Eggermann T, Algar E, Lapunzina P, Mackay D, Maher ER, Mannens M, et al. Clinical utility gene card for: Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2014;22(3). 37. Mackay D, Bens S, Perez de Nanclares G, Siebert R, Temple IK Clinical utility gene card for: transient Neonatal Diabetes Mellitus, 6q24-related. Eur J Hum Genet. 2014;26. doi:10.1038/ejhg.2014.27. 38. Buiting K, Cassidy SB, Driscoll DJ, Gillessen-Kaesbach G, Kanber D, Tauber M, et al. Clinical utility card for: Prader-Willi syndrome. Eur J Hum Genet. 2014; 16. doi:10.1038/ejhg.2014.66. 39. Buiting K, Clayton-Smith J, Driscoll DJ, Gillessen-Kaesbach G, Kanber D, Schwinger E, et al. Clinical utility gene card for: Angelman syndrome. Eur J Hum Genet. 2014;4. doi:10.1038/ejhg.2014.93. 40. Mantovani G, Linglart A, Garin I, Silve C, Elli FM, de Nanclares GP. Clinical utility gene card for: pseudohypoparathyroidism. Eur J Hum Genet. ", "Submit your next manuscript to BioMed Central and take full advantage of: ", "• Convenient online submission ", "• No space constraints or color figure charges ", "• Immediate publication on acceptance " ]

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[ "Prevalence of cognitive impairment in individuals aged over 65 in an urban area: DERIVA study ", "Emiliano Rodríguez-Sánchez1*, Sara Mora-Simón1, María C Patino-Alonso3, Ricardo García-García2, Alfonso Escribano-Hernández1, Luis García-Ortiz1, Ma Victoria Perea- Bartolomé2 and Manuel A Gómez-Marcos1 ", "Abstract ", "Background: Few data are available on the prevalence of cognitive impairment (CI) in Spain, and the existing information shows important variations depending on the geographical setting and the methodology employed. The aim of this study was to determine the prevalence of CI in individuals aged over 65 in an urban area, and to analyze its associated risk factors. ", "Methods: Design: A descriptive, cross-sectional, home questionnaire-based study; Setting: Populational, urban setting. Participants: The reference population comprised over-65s living in the city of Salamanca (Spain) in 2009. Randomized sampling stratified according to health district was carried out, and a total of 480 people were selected. In all, 327 patients were interviewed (68.10%), with a mean age of 76.35 years (SD: 7.33). Women accounted for 64.5% of the total. Measurements: A home health questionnaire was used to obtain the following data: age, sex, educational level, family structure, morbidity and functionality. All participants completed a neuropsychological test battery. The prevalence data were compared with those of the European population, with direct adjustment for age and sex. Diagnoses were divided into three general categories: normal cognitive function, cognitive impairment - no dementia (CIND), and dementia. ", "Results: The prevalence of CI among these over-65s was 19% (14.7% CIND and 4.3% dementia). The age-and sexadjusted global prevalence of CI was 14.9%. CI increased with age (p < 0.001) and decreased with increasing educational level (p < 0.001). Significant risk factors were found with the multivariate analyses: age (OR = 1.08, 95% CI: 1.03-1.12), anxiety-depression (OR = 3.47, 95%CI: 1.61-7.51) and diabetes (OR = 2.07, 95%CI: 1.02-4.18). In turn, years of education was found to be a protective factor (OR = 0.79, 95%CI: 0.70-0.90). Although CI was more frequent among women and in people living without a partner, these characteristics were not significantly associated with CI risk. ", "Conclusions: The observed raw prevalence of CI was 19% (14.9% after adjusting for age and sex). Older age and the presence of diabetes and anxiety-depression increased the risk of CI, while higher educational level reduced the risk. ", "Background ", "The prevalence of neurodegenerative diseases increases with age [1,2]. Considering that the Spanish population is among the oldest in the world (particularly the Autonomous Region of Castilla y León, where 22.5% of the inhabitants are aged over 65) [3], a substantial increase in the prevalence of cognitive impairment (CI) is to be expected in the coming years. ", "It is difficult to estimate prevalence figures for CI, since the diagnostic criteria are imprecise [4,5]. Indeed, the published dementia prevalence data for both Spain [2,6-8] and other European countries [1,9,10] show great variation. Therefore, it is not possible at present to provide reliable figures applicable to our setting. Although direct age-adjusted comparisons have been made among the different study populations, there are other influencing variables with greater adjustment problems, such as the setting (rural-urban), living in the home or in institutions, the diagnostic criteria used [11], or educational level. Also, more recent attempts to " ]

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[ "Study design ", "Training of the evaluators ", "The principal researcher coordinated the entire process. The evaluators were four psychologists trained by one of the researchers (SMS) to carry out the interview with the programmed questionnaires. A manual was drafted, describing the appointment procedure and application of the interviews, and was reviewed with the interviewers over two sessions. We also used two recorded home interviews in the training sessions. During the study, communication was permanently maintained for resolving any doubts or dealing with incidents in relation to the questionnaires. ", "Data sources ", "The sample was taken from the Castilla y León Regional Health Service lists, which cover 99.5% of the population. The lists included both community dwellers and institutionalized elders. ", "reformulate the constructs propose a clinical spectrum of CI ranging from mild cognitive impairment through dementia and a corresponding physio-pathological substrate believed to be responsible for the clinical symptoms [4,5]. The analysis of interventions that may prove effective in preventing the problems associated with CI is generating much interest, since the established therapies applied to CI are scarcely effective. However, the data available on the prevalence of CI in Spain are even more limited than in the case of dementia, and show important variations depending on the geographical setting and the methodology employed. ", "The present study carry out to estimate the prevalence of CI in the urban population over 65 years of age in the city of Salamanca (Spain), and to describe the factors associated with CI. ", "Methods ", "An observational, descriptive, cross-sectional population study. ", "Setting ", "The reference population was that of the city of Salamanca, with 172,375 inhabitants, of which 19.74% (34,020) were aged over 65. It includes 10 healthcare areas, each with a population of between 9,000 and 26,000 inhabitants. ", "Participants ", "We selected all those aged over 65 on 1 January 2009 and living in the city of Salamanca (urban setting). A door-to-door population-based survey was carried out during the months of May to November 2009. Two weeks before the interviews, letters were sent to the selected individuals, explaining the purpose of the study and requesting their cooperation. Confidentiality of data was guaranteed. Ten days after sending the letters, a telephone call was made to arrange a home interview. ", "The following exclusion criteria were applied ", "1) deceased individuals; 2) errors in address: a) when the letter was returned, or when the selected person or some reliable informer could not be located after 4 visits to the home or 4 telephone calls on different dates and at different times; b) persons who had moved out of the study area; and 3) those individuals who declined to participate in the study. ", "Ethical aspects ", "The protocol was approved by the Research Ethics Committee of Salamanca University Hospital. Participants signed the consent document after receiving the first explanatory letter providing information on the study. ", "Study size ", "Accepting an alpha risk of 0.05 and a beta risk of 0.20, estimating a CI prevalence of about 16% [12], with an error of 4%, and considering the current population aged over 65, a total of 320 patients was required. Assuming a loss rate of up to 50% due to nonresponses, as observed in similar studies, the calculated sample size was 480 individuals. In the secondary analysis of cases and controls, with a 327 participants sample, the statistical power was of 79.4% to detect an Odds Ratio of 2.5 with a confidence level of 95% (Epidat 4.0). We carried out a stratified random sampling by health districts. In order to reach the required sample size, we made a replacement for lost participants. The sample size of each health district was proportional to its population over 65 years. In a first stage, 260 interviews were carried out, accounting for 80% of the required sample. Two months later, in a second stage, we replaced the losses within each health district and 67 more people were interviewed. The most common cause of losses was patient refusal to participate (83.0%). This was particularly the case among the younger individuals (mean age: 75.94 ± 7.01 years) (p < 0.001). In turn, 12 patients were excluded because they had moved out of the study district (7.8%), while 14 had died (9.2%) (Figure 1). There were no significant differences between sexes regarding the cause of losses, or between losses in the first and second recruitment stages. Non-responders represented 34.83% of the males and 30.13% of the females. The distribution by age groups is shown in Table 1. Mean age of the males was 76.61 years (SD: ± 7.65), versus 77.52 years (SD: ± 7.92) in the females. There were no differences in distribution between the different sex and age categories. A total of 327 participants were interviewed, representing 68.1% of those " ]

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[ null, "Figure 1 Flow chart of the DERIVA Study. ", "Table 1 Distribution according to gender and different age ranks of interviewed and lost sample population. ", "occupation before retirement was defined as domestic chores, full-time job, others (part-time job, long-term unemployment, etc.). The Katz Index of Independence in Activities of Daily Living (Katz ADL) was applied to assess functional status as a measure of patient ability to perform activities of daily living (ADLs) independently [15]. This test provides information on dependence or independence, not only in terms of the number of areas, but also identifying the specific areas. The information obtained is of a qualitative and descriptive nature, and does not provide a total score on the person’s functional state. ", "At the beginning of the interview, neuropsychological assessment of patient cognitive status was carried out using a brief neuropsychological test battery including the State Examination (MMSE) [16] in its validated Spanish version [17] to evaluate general cognitive state, with the possibility of assessing cognitive functions separately; the 7 Minute following: Mini-Mental ", "selected (Figure 1). Of these, 116 were men (35.5%) and 211 were women (64.5%), with a mean age of 76.35 years (SD:± 7.33) similar in the two sexes. ", "Measurements ", "A health questionnaire was administered (OARS Multidimensional Functional Assessment Questionnaire) [13] in the participant’s home, for obtaining data on sociodemographics (age, sex, marital status), years of education, basic and instrumental activities of daily living, personal situation (people living with the patient, number of living offspring), morbidity (Charlson comorbidity index [14]), drug use and neuropsychological aspects. Marital status was classified according to whether the person was living with or without a partner (widowed, single, separated), while educational level was classified as follows: illiterate (failure to complete basic education), primary-secondary education (4-9 years of education) and higher education (over 9 years). Regular professional ", null ]

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[ "Screen [18] in its validated Spanish version [19] also to evaluate general cognitive state, as well as temporal orientation, memory, constructive praxias and language, separately; the Benton temporal orientation test [20] to evaluate temporal orientation; the Enhanced cued recall test [21] to evaluate episodic memory; the Clock drawing test [22] to evaluate constructive praxias; and the Categorical fluency task [23] to evaluate language. The cut-off points for cognitive impairment established for each test are as follows: MMSE<24; 7MS≤ percentile 20; Benton temporal orientation test ≤ 102; Enhanced cued recall test ≤ 12; Clock drawing test <3; Verbal fluency ≤ 10. ", "During the structured interview, participants were asked to present whatever relevant clinical records they might have, together with details of their current medications. In the 16 patients who were unable to complete the neuropsychological evaluation because of a deteriorated clinical condition - heart failure (2 cases), deafness (4 cases), severely impaired vision (2 cases) or severe mental impairment (4 cases) - the clinical and objective data were collected from the presented documentation, or by interviewing the caregiver or informant who knew the individual. We considered as reliable informants, in order of preference, a family member living in the same house as the individual (spouse, son/daughter, sibling); a person responsible for the care of the individual; someone living in the same house but not a family member; or a relative of the person not living in the same house. At the end of the interview the interviewers drafted a report on the quality of the information collected and on the social and health conditions of the person interviewed. Seventeen participants lived in homes for the elderly (5.2%). All the information was evaluated by the researchers (ERS, SMS, RGG and MVP) with a view to establishing the final diagnosis. The diagnoses were divided into three general categories: normal cognitive function, cognitive impairment - no dementia (CIND), and dementia. ", "Classified as cognitive impairment - no dementia (CIND) ", "CIND was defined as: 1) mild cognitive or functional impairment reported by the participant or informant that did not meet criteria for dementia; or 2) performance on neuropsychological or functional measures that was both below expectations and ≥ 0.5 standard deviations below published norms on any test [24]. ", "Classified as dementia ", "A diagnosis of dementia was made based on the Diagnostic and Statistical Manual of Mental Disorders (IV Edition) criteria: the participant must present the development of multiple cognitive deficits including memory impairment and impairment in at least one other ", "cognitive domain representing a decline from the previous level of functioning and of sufficient severity to cause impairment in function [4,5]. At a functional level, the person must present dependence in at least two functional areas, leading to interference in basic activities of daily living. Alterations at both the cognitive and functional levels were indicated by low performance and scores below the cut-off points in the neuropsychological and functional tests. As regards functional state, the person must present a minimum level of alteration in at least two functional areas. All of this must be accompanied by concern on the part of the participants about a change at a cognitive level compared to his or her previous state [4,5,25]. ", "Statistical analyses ", "The raw prevalence of CIND and dementia were calculated taking into account the total cases of CIND and dementia with respect to the total study sample. We estimated both global prevalence and specific prevalence per age group, sex, educational level, morbidity and functionality. Calculation was made of the 95% confidence intervals (95%CI) for the global and specific prevalence, together with prevalence adjusted for age and sex, using the European standard population [26] as a basis for adjustment (weighting: 36.4, 27.3, 18.2, 9.1 and 9.1 for age intervals of 65-69, 70-74, 75-79, 80-84 and = 85 years, respectively). ", "The continuous variables were expressed as the mean ± standard deviation (SD), while frequency distributions were used for the qualitative variables. Logistic regression analysis was used to explore the sociodemographic, functional and clinical factors independently associated with the presence of CIND/dementia. The enter method was used in a first step to include the adjusting variable (patient age and sex), followed in a second step by the stepwise method in application to the rest of the independent variables: years of education, educational level, Katz index, living with partner, restlessness, anxiety or depression, sleeping problems or insomnia, diabetes and Charlson comorbidity index. The dependent variable was cognitive impairment (CI)(code 0: no CI; code 1: presence of CI), while in the case of the independent variables the reference groups were male sex, illiteracy, absence of diabetes, no insomnia, no depression, and living without a partner. Patient age, the Katz index, years of education and the Charlson comorbidity index were taken as continuous variables. The data were analyzed using the SPSS/PC+ version 18.0 statistical package (SPSS Inc., Chicago, IL, USA). ", "Results ", "Table 2 shows the raw, age-adjusted and age-and sexadjusted prevalence of CIND (48 participants, 14.7%) " ]

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[ "Table 2 Crude, age-adjusted, and age- and sex-adjusted prevalence of dementia and cognitive impairment (CI). ", null, "aAge standardization weights European Standard: 36.4, 27.3, 18.2, 9.1 and 9.1 for 65-69, 70-74, 75-79, 80-84 and ≥85, respectively; sex standardization weight: 0.50 (sources: http://www.wmpho.org.uk/localprofiles/metadata.aspx?id=META_EUROSTD) [26]; bEstimated number of subjects in hundreds with de disease based on age- and sex-adjusted prevalence (Salamanca h ≥65 years 2009 estimated population: 34.020h. (source: Castilla and León Regional Health Service lists. CIND: cognitive impairment not dementia; CI, confidence interval; PE, prevalence point-estimate; PP, crude prevalence ratio (cases divided by population). ", "and dementia (14 participants, 4.3%). In total, 62 of the 327 participants studied (19.0%) suffered from CI (CIND or dementia). On standardizing for age, the prevalence decreased similarly in men and women - the estimated adjusted prevalence being 16.1% (95%CI: 11.620.6), versus 14.9% when adjusted for age and sex. The prevalence of CIND and dementia increased with age (p < 0.001), and women were seen to predominate among the individuals with CIND (79.16%) and in those with dementia (71.42%) (Figure 2). The 14 patients classified as presenting dementia had a mean age of 79.35 years (SD = 7.33), and in 8 cases (57.14%) the cause ", "corresponded to Alzheimer’s disease (AD), in 3 cases (21.43%) to probable vascular disorders, and in 3 cases (21.43%) to a mixture of factors. ", "Table 3 shows the characteristics of the 327 DERIVA study participants, stratified by cognitive status. Mean age was lower in the normal cognition group, while educational level was higher. The patients with CI had lower Charlson comorbidity scores. Figure 3 shows the prevalence of CIND according to educational level and the functional clinical and neuropsychological characteristics of the participants. The prevalence of CI among the illiterate participants was 34%, versus 25.5% among " ]

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[ null, "Figure 2 Crude, age-adjusted and age- and sex-adjusted prevalence of CIND and dementia. ", "the patients living without a partner. The prevalence of CI among the individuals with depression, insomnia, hypercholesterolemia or diabetes was over 27%. In turn, 10.4% of the participants who were independent for their activities of daily living (ADLs) as assessed with the Katz index suffered from CI, versus 26.9% of the participants found to be dependent for two or more ADLs. ", "Significant predictor factors were found with the multivariate analyses: age (OR = 1.08, 95%CI: 1.03-1.12), anxiety-depression (OR = 3.47, 95%CI: 1.61-7.51), diabetes (OR = 2.07, 95%CI: 1.02-4.18) and educational level (OR = 0.79, 95%CI: 0.70-0.90) (Table 4). ", "Discussion ", "The observed prevalence of 14.7% for CIND and 4.3% for dementia implies a total of 19% of all people aged over 65 with CI in the city of Salamanca in 2009. The age-adjusted and age-and sex-adjusted overall prevalence (CIND or dementia) was 14.9% (95%CI: 10.6-19.2). The prevalence of CI increased with age and decreased with increasing educational level. Although CI was more frequent among women and in people living without a partner, these characteristics were not significantly associated with CI risk. Significant risk factors were found with the multivariate analyses: age, anxiety-depression and diabetes, while years of education proved to be a protective factor. ", "Few population-based studies of CI have been published in Spain. Adequate comparisons are therefore difficult to make, though our data are within the lower range of other Spanish studies (13.8-35.2%) [27-31] and European surveys [1,10,32]. A possible explanation for this relatively low prevalence may be the fact that our study was conducted in an urban setting. Large differences have been found among different Spanish regions. In this regard, Murcia yielded a CIND prevalence of 13.8% in the urban setting, versus 23.3% in the rural zone [27]. Nunes et al. [10], in an urban setting in the north of Portugal, reported a lower prevalence of CI (12.0%), though these authors included a younger age group (55 to 79 years). The raw prevalence of CI found in our study is lower than the 22.2% reported for the United States [24,33] or the 16.8% prevalence of CIND and 8% prevalence of dementia estimated for Canada [12]. ", "In our study we took into account the most up-todate diagnostic criteria [4,5,24] according to which it is considered that CIND can involve alteration in various higher cognitive functions, and not only in memory. Therefore, we should have obtained higher figures than if we had considered the criteria of Petersen et al [34]. On the other hand, however, the Katz ADL Index is less sensitive for assessing ADLs than for assessing more complex activities. ", "The literature offers more references to the prevalence of dementia, though consensus in this case is likewise " ]

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[ "Table 3 Sociodemographic, functional, clinical and neuropsychological characteristics of the participants according to cognitive impairment (CI). ", null ]

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[ "Table 3 Sociodemographic, functional, clinical and neuropsychological characteristics of the participants according to cognitive impairment (CI). (Continued) ", null, "CI: cognitive impairment (CIND or dementia); MMSE: Minimental State Examination. #: Mean ± Standard deviation p: Statistically significant differences between the two groups MMSE: Mini-Mental State Examination score. ", "lacking regarding the true figures applicable to Spain. Nevertheless, it has been suggested that the prevalence in this country is lower than in other regions of Europe. Our data point to an adjusted dementia prevalence in the city of Salamanca of 3.3%, which is close to the lowest estimates both in Spain [2,6] and in Europe [32]. Crude dementia prevalence for elders aged 70 years and over range from 5% in Murcia [27] to 17.2% in Pamplona [2]. ", "Recent publications suggest that the number of individuals with CIND in the United States is about 70% higher than the number with dementia. In the 71- to 79-year-old age group, 16% had CIND, whereas an additional 5% had dementia. A similar proportion was found in the recent Mexican Health and Aging Study [35], though the prevalence figures are slightly higher: 6.1% for CIND as against 28.7% for dementia. Another possible reason why these differences cannot be explained is the threshold set, since, as Seshadri et al. [36] pointed out, depending on where the differential threshold is placed, the percentages of CIND and dementia will vary. It should also be borne in mind that when a report is requested from an informant about the person’s functional limitations, the prevalence is substantially lower [2,6,11] ", "It must be taken into account that the study was designed to determine the global prevalence of CI, and that the estimation of dementia prevalence would require a larger sample. These results therefore must be viewed with caution. The study was carried out in a random sample of the population of the city that included people living in homes for the elderly, and since the prevalence of dementia in these institutions is higher than in the community [12] the possible associated bias has been avoided. However, the percentage distribution according to the most likely etiology coincides with the data of most other reports - Alzheimer’s disease accounting for over one-half of the cases, followed by vascular dementia. ", "At present, evaluation of the existing data is the subject of even greater debate than the publication of new ", "data [2,24,34,35,37]. It has been reported that the estimates of probable dementia are higher in surveys than in meta-analyses for the 65-84 year age interval, but similar among individuals aged 85 years and older [38]. In our study we obtained sufficient information in the context of a health survey, including evaluations of patient functionality and clinical and neuropsychological conditions, to determine the cognitive status of each participant [13]. Such information is therefore more relevant than that derived only from the application of a battery of tests. The diagnostic criteria employed are similar to those used in recent epidemiological studies [33,36] with the purpose of obtaining results that can be compared with those collected in other settings, and also of examining the tendencies in disease prevalence in a single district in relation to morbidity among the elderly, healthcare, social support and economic resources. In accordance with the current recommendations for conducting epidemiological studies, on including patients with cognitive impairment, we placed priority on the inclusion of all individuals who possibly presented such impairment - since it was not our main objective to analyze the types or the severity of dementia. In other words, we placed greater emphasis on the use of those evaluating instruments affording greater sensitivity, at the cost of lesser specificity. Those surveys based only on the detection of dementia can underestimate the true incidence of neurodegenerative diseases in their milder stages. Considering all of the above, it is even more striking that the CI prevalences found are among the lowest published to date. There is no consensus regarding which functionality scales and neuropsychological batteries [39] are best suited to use in epidemiological studies in dementia, despite the fact that both elements have classically been used in diagnosing the disease [34]. It is exceptional for prevalence studies to specify how functionality has been evaluated [8], though we agree with Thomas et al. [40], who recommended the incorporation of functional disability data as a complement to studies estimating the " ]

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[ null, "Figure 3 Prevalence of CIND, CI or dementia according to level of studies, the features functional, clinical and neuropsychological participants. ", "prevalence and severity of CI in the community. In our study, functionality was evaluated with the Katz ADL index, which is widely used to evaluate elderly people in an objective manner, and is therefore adequate for establishing comparisons among different populations. Among the participants of the DERIVA study, only 45.30% of those classified as not presenting CI, versus 22.60% of those classified as presenting CI, preserved functionality in all the areas evaluated by the Katz ADL ", "index. Disability is common among people over 65 years of age; as a result, the way in which disability is evaluated exerts a strong influence when it is considered in the diagnosis of CI. Both the Lawton PSMS-IADL and the Katz scales remain widely used in psychosocial intervention research, and are easy to complete. The PSMSIADL is not as popular as the Katz index, but has an option for patient self-report. The Katz and PSMS-IADL have been used widely in anti-dementia drug studies " ]

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[ "Table 4 Variables associated with presenting cognitive impairment (CI): OR and 95 confidence intervals for total CIND/dementia vs. Controls/Healthy. ", null, "and in some psychosocial intervention studies in both North America and Europe [41,42]. Although the classical criteria of mild cognitive impairment (MCI) [34] excluded the presence of important functional deficits, the need to revise this approach has recently been suggested [43]- particularly when distinguishing between dementia and CIND, where different types of impairment are included [44]. Difficulties remembering appointments, telephone numbers, family meetings, holidays, medicines or domestic economics, or running businesses or filling out certain documents, can all be useful for suspecting early-stage CI [45]. Although less extensively studied, it is also necessary to consider statistical analyses of the results obtained with the different tests, taking into account that patient problems in obtaining better scores are not always attributable to CI. As an example, it has been described that 11 of the 30 items of the MMSE show high variability due to aspects unrelated to the degree of CI. Therefore, the MMSE would not be recommended as an instrument for use in screening for dementia among patients with Parkinson’s disease [46]. ", "The importance of certain personal factors ", "Our data coincide with those of practically all studies regarding the increase in CI with advancing age (Figure 2). It has been estimated that between 65 and 85 years of age, the prevalence doubles every 5.2 years, in an exponential manner [47]. However, there is no general agreement regarding prevalence in terms of patient sex. The condition is rarely associated with the male sex [48], while in contrast many studies have associated dementia with the female sex [2,29,31,49,50], since women predominate in descriptive studies, and a correlation is found in the bivariate analyses, in accordance with our own observations. However, on considering other variables such as age, educational level or comorbidity, this relationship disappears. Our data would support the idea that dementia is not associated with women [1,25,27,33,47]. In coincidence with our own study, many authors [7,33,51] have described an inverse relationship between the prevalence of CI and a lower educational level. Thus, it has been suggested that these ", "differences could be related to certain biological mechanisms that would be responsible for this association [8,27,29,52,53]. However, a recent epidemiological study based on 875 necropsies revealed no protective effect of the years of education received in early stages in life in relation to the accumulation of neurodegenerative or vascular pathologies of the brain [54]. Even so, it has been suggested that when the disease affects people with higher educational level, the manifestations are milder, being mitigated by a greater coping capacity thereby postponing their consequences for a period of time. It remains to be clarified whether educational levels developed in later periods in life may or may not affect the development of dementia. In an attempt to offer information on this issue, we analyzed the type of regular professional activity of the DERIVA study patients before retirement, though no relationships were found. Perhaps a different classification of activity, analyzing those which may contribute most to intellectual development, could help identify a relationship. Regarding the family situation, we found that those participants living with their partner showed a 13.7% lower prevalence of CI than those living without a partner (p = 0.007). This is in agreement with the observations of Helmer [55], who found single individuals to have a greater risk of suffering dementia than married people. In our case there were no differences related to the fact of living alone or with one or more people, in terms of the prevalence of CI. As ours is a cross-sectional study, however, neither of these characteristics offers information for clarifying whether the current situation is a consequence of or a risk factor for the development of CI. ", "Many chronic illnesses can be found in elderly people. The Charlson score was greater among the individuals with CI (p = 0.004), though the multivariate analysis did not find it to behave as a risk factor for CI. The association between diabetes (p = 0.045) and dementia has already been described in classic studies [52], though it must be mentioned that while arterial hypertension is accepted as being more closely associated with stroke [31,51], diabetes is the disease found to be associated with CI in the logistic regression analyses. The association between CI and diabetes, as well as the absence of an association with arterial hypertension and hypercholesterolemia, coincide with the findings in another Spanish region [56]. It appears that brain damage would be related to vascular mechanisms [33,37], and since the prevalence of these cardiovascular diseases is not homogeneous in all regions, they should be considered in CI prevalence studies with a view to establishing comparisons. People with CI more often have sleeping problems (p = 0.027) and anxiety-depression (p < 0.001), though only the latter was seen to behave as a CI risk factor in the multivariate analysis. In coincidence with Johansson " ]

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[ "et al. [57], we found an association between psychological stress and CI, though in the study by the mentioned authors this association was detected in middle-aged women. ", "Among the limitations of our study, mention must be made of the lack of consensus on the precise criteria involved in making comparisons between different epidemiological studies. Another common and important limitation in studies of this kind is the possible loss of the more seriously deteriorated individuals, since it has been shown that those people who refuse to participate are more likely to have more seriously impaired cognitive function [58] - a situation which may introduce bias and alter the prevalence data obtained. A further limitation of the study is that since the evaluations were carried out by four different psychologists, inter-observer reliability may be affected. However, each evaluation was followed by an appraisal of the interview with a view to tests correction and the reduction of possible bias. Among the strengths of the study, we should mention the inclusion of a representative sample from the city of Salamanca, as well the proposal to incorporate functional evaluation and the clinical processes influencing the prevalence of CI [5]. The study cohort would permit a longitudinal evaluation of CIND, and the longterm results may contribute to identifying the characteristics of those individuals who develop dementia. ", "Conclusions ", "The observed raw prevalence of CI was 19% (14.9% after adjusting for age and sex), and corresponds to the lower range of the prevalence estimated at both national and international level. Older age and the presence of diabetes and anxiety-depression increased the risk of CI, while higher educational level reduced the risk. ", "List of abbreviations ", "AD: Alzheimer’s disease; BADL: basic activities of daily living; CI: Cognitive Impairment; CIND: Cognitive impairment - no dementia. ", "Acknowledgements ", "This project was supported by the INFOSALUD Foundation, Castilla-León Health Service (GRS 270/A/08 and BIO39/SA04/10), ISCIII (RD06/018/27), and Vicente- García Corselas Foundation (University of Salamanca). ", "Author details ", "1Primary care research unit of La Alamedilla Health Center, Castilla y León Health Service- SACYL, Salamanca, Spain. 2Department of Basic Psychology, Psychobiology and Behavioral Sciences Methodology. Faculty of Psychology. University of Salamanca. Spain. 3Department of Statistics. Faculty of Medicine. University of Salamanca. Spain. ", "Authors’ contributions ", "Conception of the idea for the study: ERS, RGG, LGO, MGM and MVP. Development of the protocol and organization: ERS, SMS, CPA and AEH. Participated in the design of the study and performed the statistical analysis: ERS, SMS, CPA and AEH. Writing of the manuscript: ERS, SMS CPA and LGO. All the authors have read the draft critically, so as to make contributions, ", "and have approved the final text. The project was developed by the Primary Care Research Unit at La Alamedilla Health Centre, Salamanca. Spain. ", "Competing interests ", "The authors declare that they have no competing interests. ", "Received: 12 August 2011 Accepted: 17 November 2011 Published: 17 November 2011 ", "Fratiglioni L: Occurrence of cognitive impairment and dementia after the age of 60: a population-based study from Northern Italy. Dement Geriatr Cogn Disord 2005, 19(2-3):97-105. de Pedro-Cuesta J, Virues-Ortega J, Vega S, Seijo-Martinez M, Saz P, Rodriguez F, Rodriguez-Laso A, Rene R, de las Heras SP, Mateos R, MartinezMartin P, Manubens JM, Mahillo-Fernandez I, Lopez-Pousa S, Lobo A, Regla JL, Gascon J, Garcia FJ, Fernandez-Martinez M, Boix R, BermejoPareja F, Bergareche A, Benito-Leon J, de Arce A, del Barrio JL: Prevalence of dementia and major dementia subtypes in Spanish populations: a reanalysis of dementia prevalence surveys, 1990-2008. BMC Neurol 2009, 9:55. INE: Instituto Nacional de Estadística: Datos de población en España. [http://www.ine.es], (15/05/2011). 2. 3. 4. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH: The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011, 7(3):263-269. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH: The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011, 7(3):270-279. Virues-Ortega J, de Pedro-Cuesta J, Vega S, Seijo-Martinez M, Saz P, Rodriguez F, Rodriguez-Laso A, Rene R, de Las Heras SP, Mateos R, Martinez-Martin P, Mahillo-Fernandez I, Lopez-Pousa S, Lobo A, Regla JL, Gascon J, Garcia FJ, Fernandez-Martinez M, Boix R, Bermejo-Pareja F, Bergareche A, Sanchez-Sanchez F, de Arce A, del Barrio JL: Prevalence and European comparison of dementia in a >/=75-year-old composite population in Spain. Acta Neurol Scand 2011, 123(5):316-324. Gascon-Bayarri J, Rene R, Del Barrio JL, De Pedro-Cuesta J, Ramon JM, Manubens JM, Sanchez C, Hernandez M, Estela J, Juncadella M, Rubio FR: Prevalence of dementia subtypes in El Prat de Llobregat, Catalonia, Spain: the PRATICON study. Neuroepidemiology 2007, 28(4):224-234. Escudero Sanchez C, Garcia Carmona R, Ibanez Colas A, Lopez Lopez MA, Hidalgo Garcia-Consuegra MA, Perez Juarez A, Salan Garcia M, Utrilla Bermejo F: [Cognitive deficit, its prevalence and associated factors in the population over 74]. Aten Primaria 1999, 24(6):326-331. Ankri J, Poupard M: [Prevalence and incidence of dementia among the very old. Review of the literature]. Rev Epidemiol Sante Publique 2003, 51(3):349-360. 5. 6. 7. 8. 9. 10. Nunes B, Silva RD, Cruz VT, Roriz JM, Pais J, Silva MC: Prevalence and pattern of cognitive impairment in rural and urban populations from Northern Portugal. BMC Neurol 2010, 10:42. 11. Wilson R, David R, Weir D, Leurgans S, Evans D, Hebert L, Langa K, Plassman B, Small B, Bennett D: Sources of variability in estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimers Dement 2011, 7:74-79. 12. Graham JE, Rockwood K, Beattie BL, Eastwood R, Gauthier S, Tuokko H, McDowell I: Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet 1997, 349(9068):1793-1796. 13. Grau Fibla G, Eiroa Patino P, Cayuela Dominguez A: [Spanish version of the OARS Multidimensional Functional Assessment Questionnaire: crosscultural adaptation and validity measurement]. Aten Primaria 1996, " ]

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[ "15. Wallace MS: Mary Katz Index of Independence in Activities of Daily Living (ADL). Assisted Living Consult 2008, 2:21-22. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975, 12(3):189-198. Escribano-Aparicio MVP-DM, García-García FJ, Pérez-Martín A, Romero L, Ferrer G, Martín-Correa E, Sánchez-Ayala MI: Validación del MMSE de Folstein en una población española de bajo nivel educativo. Rev Esp Geriatr Gerontol 1999, 34(6):319-326. Solomon PR, Hirschoff A, Kelly B, Relin M, Brush M, DeVeaux RD, Pendlebury WW: A 7 minute neurocognitive screening battery highly sensitive to Alzheimer’s disease. Arch Neurol 1998, 55(3):349-355. 19. del Ser Quijano T, Sanchez Sanchez F, Garcia de Yebenes MJ, Otero Puime A, Zunzunegui MV, Munoz DG: [Spanish version of the 7 Minute screening neurocognitive battery. Normative data of an elderly population sample over 70]. Neurologia 2004, 19(7):344-358. 20. Benton A: Contributions to Neuropsychological Assessment. New York, NY: Oxford University Press Inc; 1983. 21. Grober E, Buschke H, Crystal H, Bang S, Dresner R: Screening for dementia by memory testing. Neurology 1988, 38(6):900-903. Freedman M LL, Kaplan E, Winocur G, Shulman KI, Delis D: Clock Drawing: A Neuropsychological Analysis. New York, NY: Oxford University Press Inc; 1994. 23. Goodglass H KE: Evaluación de la afasia y de trastornos relacionados. Madrid: Panamericana; 1986. 24. Brookmeyer R, Evans DA, Hebert L, Langa KM, Heeringa SG, Plassman BL, Kukull WA: National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimers Dement 2011, 7(1):61-73. 25. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB: Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med 2008, 148(6):427-434. 26. WMPHO: West Midlands Public Health Observatory.The European Standard Population.[http://www.wmpho.org.uk/localprofiles/metadata. aspx?id=META_EUROSTD]. 27. Gavrila D, Antunez C, Tormo MJ, Carles R, Garcia Santos JM, Parrilla G, Fortuna L, Jimenez J, Salmeron D, Navarro C: Prevalence of dementia and cognitive impairment in Southeastern Spain: the Ariadna study. Acta Neurol Scand 2009, 120(5):300-307. 28. Bufill E, Bartes A, Moral A, Casadevall T, Codinachs M, Zapater E, Rovira JC, Perez R, Roura P, Blesa R: [Prevalence of cognitive deterioration in people over 80-years-old: COGMANLLEU study]. Neurologia 2009, 24(2):102-107. 29. Graciani A, Banegas JR, Guallar-Castillon P, Dominguez-Rojas V, RodriguezArtalejo F: Cognitive assessment of the non-demented elderly community dwellers in Spain. Dement Geriatr Cogn Disord 2006, 21(2):104-112. Limon Ramirez E, Argimon Pallas JM, Vila Domenech J, Abos Pueyo T, Cabezas Pena C, Vinyoles Bargallo E: [Detection of cognitive impairment in the population of persons older than 64 years: first phase of the Cuida’l project]. Aten Primaria 2003, 32(1):6-12. 31. Millan-Calenti JC, Tubio J, Pita-Fernandez S, Gonzalez-Abraldes I, Lorenzo T, Maseda A: Prevalence of cognitive impairment: effects of level of education, age, sex and associated factors. Dement Geriatr Cogn Disord 2009, 28(5):455-460. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M: Global prevalence of dementia: a Delphi consensus study. Lancet 2005, 366(9503):2112-2117. 33. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB: Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007, 29(12):125-132. 34. Petersen RC, Roberts RO, Knopman DS, Boeve BF, Geda YE, Ivnik RJ, Smith GE, Jack CR Jr: Mild cognitive impairment: ten years later. Arch Neurol 2009, 66(12):1447-1455. 35. Mejia-Arango S, Gutierrez LM: Prevalence and incidence rates of dementia ", "36. Seshadri S, Beiser A, Au R, Wolf PA, Evans DA, Wilson RS, Petersen RC, Knopman DS, Rocca WA, Kawas CH, Corrada MM, Plassman BL, Langa KM, Chui HC: Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment-Part 2. Alzheimers Dement 2011, 7(1):35-52. Shin HY, Chung EK, Rhee JA, Yoon JS, Kim JM: [Prevalence and related factors of dementia in an urban elderly population using a new screening method]. J Prev Med Public Health 2005, 38(3):351-358. 37. 38. Anstey KJ, Burns RA, Birrell CL, Steel D, Kiely KM, Luszcz MA: Estimates of probable dementia prevalence from population-based surveys compared with dementia prevalence estimates based on meta-analyses. BMC Neurol 2010, 10:62. 39. Maruta C, Guerreiro M, de Mendonca A, Hort J, Scheltens P: The use of 40. neuropsychological tests across Europe: the need for a consensus in the use of assessment tools for dementia. Eur J Neurol 2011, 18(2):279-285. Thomas VS, Darvesh S, MacKnight C, Rockwood K: Estimating the prevalence of dementia in elderly people: a comparison of the Canadian Study of Health and Aging and National Population Health Survey approaches. Int Psychogeriatr 2001, 13(Supp 1):169-175. 41. Moniz-Cook E, Vernooij-Dassen M, Woods R, Verhey F, Chattat R, De Vugt M, Mountain G, O’Connell M, Harrison J, Vasse E, Droes RM, Orrell M: A European consensus on outcome measures for psychosocial intervention research in dementia care. Aging Ment Health 2008, 12(1):14-29. 42. Olazaran J, Reisberg B, Clare L, Cruz I, Pena-Casanova J, Del Ser T, Woods B, Beck C, Auer S, Lai C, Spector A, Fazio S, Bond J, Kivipelto M, Brodaty H, Rojo JM, Collins H, Teri L, Mittelman M, Orrell M, Feldman HH, Muniz R: Nonpharmacological therapies in Alzheimer’s disease: a systematic review of efficacy. Dement Geriatr Cogn Disord 2010, 30(2):161-178. 43. Brown PJ, Devanand DP, Liu X, Caccappolo E: Functional Impairment in Elderly Patients With Mild Cognitive Impairment and Mild Alzheimer Disease. Arch Gen Psychiatry 2011, 68(6):617-626. 44. Bangen KJ, Jak AJ, Schiehser DM, Delano-Wood L, Tuminello E, Han SD, Delis DC, Bondi MW: Complex activities of daily living vary by mild cognitive impairment subtype. J Int Neuropsychol Soc 2010, 16(4):630-639. 45. Binegar DL, Hynan LS, Lacritz LH, Weiner MF, Cullum CM: Can a direct IADL measure detect deficits in persons with MCI? Curr Alzheimer Res 2009, 6(1):48-51. 46. Prieto G, Delgado AR, Perea MV, Ladera V: Scoring neuropsychological tests using the Rasch model: an illustrative example with the ReyOsterrieth Complex Figure. Clin Neuropsychol 2010, 24(1):45-56. Jorm AF, Jolley D: The incidence of dementia: a meta-analysis. Neurology 1998, 51(3):728-733. 47. 48. Henao-Arboleda E, Aguirre-Acevedo DC, Munoz C, Pineda DA, Lopera F: [Prevalence of mild cognitive impairment, amnestic-type, in a Colombian population]. Rev Neurol 2008, 46(12):709-713. 49. Yaffe K, Middleton LE, Lui LY, Spira AP, Stone K, Racine C, Ensrud KE, 50. Kramer JH: Mild cognitive impairment, dementia, and their subtypes in oldest old women. Arch Neurol 2011, 68(5):631-636. Fernandez M, Castro-Flores J, Perez-de las Heras S, MandalunizLekumberri A, Gordejuela M, Zarranz J: [Prevalence of dementia in the elderly aged above 65 in a district in the Basque Country]. Rev Neurol 2008, 46(2):89-96. 51. De Ronchi D, Palmer K, Pioggiosi P, Atti AR, Berardi D, Ferrari B, Dalmonte E, Fratiglioni L: The combined effect of age, education, and stroke on dementia and cognitive impairment no dementia in the elderly. Dement Geriatr Cogn Disord 2007, 24(4):266-273. 52. Ott A, Breteler MM, van Harskamp F, Claus JJ, van der Cammen TJ, Grobbee DE, Hofman A: Prevalence of Alzheimer’s disease and vascular dementia: association with education. The Rotterdam study. BMJ 1995, 310(6985):970-973. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R: Influence of education and occupation on the incidence of Alzheimer’s disease. JAMA 1994, 271(13):1004-1010. 53. 54. Brayne C, Ince PG, Keage HA, McKeith IG, Matthews FE, Polvikoski T, Sulkava R: Education, the brain and dementia: neuroprotection or compensation? Brain 2010, 133(Pt 8):2210-2216. 55. Helmer C: Dementia and marital status at midlife and late life. BMJ 2009, " ]

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[ "57. Fernandez Martinez M, Castro Flores J, Perez de Las Heras S, Mandaluniz Lekumberri A, Gordejuela Menocal M, Zarranz Imirizaldu JJ: Risk factors for dementia in the epidemiological study of Munguialde County (Basque Country-Spain). BMC Neurol 2008, 8:39. Johansson L, Guo X, Waern M, Ostling S, Gustafson D, Bengtsson C, Skoog I: Midlife psychological stress and risk of dementia: a 35-year longitudinal population study. Brain 2010, 133(Pt 8):2217-2224. 58. Matthews FE, Chatfield M, Freeman C, McCracken C, Brayne C: Attrition and bias in the MRC cognitive function and ageing study: an epidemiological investigation. BMC Public Health 2004, 4:12. ", "The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2377/11/147/prepub ", "Cite this article as: Rodríguez-Sánchez et al.: Prevalence of cognitive impairment in individuals aged over 65 in an urban area: DERIVA study. BMC Neurology 2011 11:147. ", "Submit your next manuscript to BioMed Central and take full advantage of: ", "• Convenient online submission ", "• Immediate publication on acceptance " ]

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[ "Assessment of a revolving drug fund for essential asthma medicines in Benin ", "Gildas Agodokpessi1, Nadia Aït-Khaled2, Martin Gninafon1, Leon Tawo1, Wilfried Bekou1, Christophe Perrin2, Karen Bissell2, Nils Billo2, Donald A Enarson2 and Chen-Yuan Chiang2,3,4* ", "Abstract ", "Objectives: Benin established a revolving drug fund (RDF) for essential asthma medicines in 2008. We evaluated the operation of the RDF and assessed whether there was interruption of supply of asthma medicine from 2008 to 2013. ", "Methods: We reviewed the process in establishing the RDF. We assessed cost and sale price of asthma medicines, expenditure of the RDF in procuring asthma medicines and other tools, revenue generated by sales of medicines to patients, and balance of capital as of 31 January 2013. We investigated whether there was interruption of supply of essential asthma medicines from 2008–2013. ", "Results: The total amount of grants initially injected into the RDF was 24,101€. As of 31 January 2013, the capital of the RDF, including the deposit in the RDF bank account (8,114€) and the value of inhalers in stock (12,172€), was equivalent to 20,586€, slightly less than the initial capital (24,101€). The decrease of capital was mainly because a number of inhalers were expired or provided free-of-charge (6,091€) and because part of the fund was used to procure other elements required for the management of asthma (4,338€). Thanks to a RDF, Benin maintained an uninterrupted supply of essential asthma medicines in asthma pilot sites from 2008–2013. ", "Conclusion: The Benin experience demonstrated that in countries where universal health coverage was not yet in place, establishment of a RDF may help maintain an uninterrupted supply of essential medicines. ", "Keywords: Asthma, Revolving drug fund, Beclometasone, Inhaled corticosteroid ", "Introduction ", "Shortage of pharmaceutical supply is common in resource-limited settings. Access to affordable essential medicines for non-communicable diseases in resource limited settings can be particularly challenging [1,2]. The low affordability of essential asthma medicines, in particular the inhaled corticosteroid (ICS), was identified as one of the main barriers in providing proper asthma care in low- and middle-income countries [2-7]. Revolving drug funds have been applied in a variety of settings to address this problem through financing drug supply [8-11]. It usually begins with an initial capital investment, ", "followed by replenishment of drug stock with monies collected from the sale of medicines. ", "A project introducing a comprehensive approach to lung health (CAL), funded by the World Bank and implemented through collaboration between the International Union Against Tuberculosis and Lung Disease (The Union) and partners in Benin, China and Sudan, included as one of its aims to reduce the burden of lung disease through management of patients with persistent asthma [12,13]. In Benin, it was implemented in 2008 at two public health facilities (Centre national hospitalier de pneumophtisiologie (CNHP) in Cotonou and one tuberculosis unit located in Porto-Novo) and three missionary health facilities. For the implementation of standard case management of asthma, it was decided to establish a revolving drug fund (RDF) for essential asthma medicines to ensure uninterrupted supply of essential asthma medicine. In this " ]

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[ "paper, we evaluated the operation of a RDF for asthma from 2008 to 2013. ", "Methods ", "Setting ", "Benin is a low income country where universal health coverage is not yet in place. Most asthma patients have had to pay out of pocket for health services. Before the asthma pilot project, the majority of asthma patients were being treated exclusively on an emergency basis when they presented with an acute attack of asthma and that only a small minority of asthma patients were prescribed with ICS in Benin [12]. ", "Establishment of a revolving drug fund for essential asthma medicine ", "Before the CAL project implementation, the Benin national tuberculosis programme (NTP) manager and The Union consultant discussed whether asthma inhalers should be provided free-of-charge to asthma patients or whether it would be more sustainable to establish a RDF for essential asthma medicines. As asthma is a chronic disease and long term management is required, maintaining uninterrupted supply of affordable asthma medicines is essential for ensuring the continuity of care. There was concern that if asthma inhalers were provided at no cost to patients, the supply of asthma inhalers might be interrupted when the project finished. Thus, part of the World Bank grant was used as an initial capital investment to establish a RDF for asthma medicines that would aim to sustain long term management of asthma in five asthma pilot sites. ", "The coordinator of the asthma projects and the RDF was the NTP manager, who was also the director of the biggest site for asthma management (the CNHP). A dedicated bank account for the RFD was created; monies collected from the sale of asthma inhalers were deposited in the RFD bank account for further procurement of asthma inhalers. ", "Initial capital of RDF ", "The initial capital invested into the CAL project in 2008 for procuring asthma medicines was 9,940€. With this, Benin’s NTP manager purchased 2,000 units each of inhaled beclometasone (200 puffs, 250 μg per puff) and of inhaled salbutamol through Benin’s central pharmacy for essential medicines (CAME). Due to a delay in delivery of medicines at the beginning of project implementation, the CAME donated 320 inhalers of beclometasone (total 1,203€), which allowed the project to commence and added to the value of the RDF. Until the ordered medicines arrived, patients had to buy inhaled salbutamol at a private pharmacy. The total grant provided to the CNHP to establish the RDF for asthma for the CAL ", "project, including the medicines donated by the CAME, was 11,143€. ", "Asthma drug facility and additional capital of RDF ", "The Union created the Asthma Drug Facility (ADF), which aimed to provide affordable access to qualityassured essential asthma medicines for low- and middleincome countries [14,15]. The ADF pooled requests from qualifying programmes for quality-assured essential asthma medicines. It used bi-yearly international competitive bids to offer the most affordable prices possible for asthma medicines after a qualification procedure ensuring the selection of inhalers in strict compliance with international quality standards. To pilot the operations of the ADF, The Union and the Benin NTP agreed that The Union would donate inhaled medicines and provide training and technical assistance for the implementation of standard case management of asthma, and that the Benin NTP would maintain the RDF for asthma to procure essential asthma medicines through the ADF for the following three years. It was agreed that a small margin should be added to the cost of the medicines procured through the ADF to cover customs clearance, storage, distribution, and potential loss of drugs, and to slightly increase the amount of the fund to ensure sustainability. The Union donated 2,500 units of inhaled beclometasone propelled by hydrofluoroalkanes (HFA) (100 μg per puff, 200 puffs) and 2000 HFA inhaled salbutamol (100 μg per puff, 200 puffs), equivalent to 7530€, to Benin through the ADF in 2010 for the implementation of the ADF pilot project. ", "In addition to medicines, both the CAL project and the ADF pilot project funded other project elements, such as training, coordination, supervision, purchase of peak flow meter, spirometers, and mouthpieces, and the printing of asthma treatment cards and treatment registers as well as posters for patient education. At the end the projects, 5,428€ remained unspent and were of injected into the RDF. ", "Maintaining the RDF ", "The CNHP was responsible for the distribution of inhalers to other pilot sites and maintaining the RDF. The sites charged patients at the selling price recommended by CNHP without adding a site margin during the first project year. All these sites agreed to conduct quarterly follow-up and to manage asthma attacks free-of-charge (the usual consultation fee was about 0.30€). After the end of the one year ADF pilot project, the three missionary sites decided unilaterally to add a site margin for the management of asthma drugs and increased the cost of both inhaled beclometasone and inhaled salbutamol by 0.3€ per inhaler, which did not return to the RDF. In March 2011, the Benin NTP Director, after discussion " ]

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[ "Table 1 Grants that contributed to Benin’s revolving drug fund, 2008–2013 ", "[17] was used in the ADF project. We reviewed registration of asthma patients for standard case management of asthma during the period 2008–2011. ", "Ethics ", "As the information collected was a part of routine health service operations in Benin, review by an ethics committee was not considered to be required. All information was handled by the health care workers who provided care for the patients on a routine basis. No individual identifiers were provided to individuals outside the health service. ", "Results ", "the total amount of grants Table 1 shows injected into the RDF over the period of 2008–2010 was 24,101€. that ", "Medicines prices for the CAL and ADF projects ", "Table 2 shows that in the CAL project the purchase price of inhaled salbutamol, propelled by chlorofluorocarbons (CFC), was 0.95€ and that of CFC inhaled beclometasone 3.50€. With a 14% margin set by the NTP, the selling price was 1.37€ for inhaled salbutamol and 4.27€ for inhaled beclometasone. ", "The cost of ADF inhaled beclometasone was 1.78€, about half of the cost of inhaled beclometasone procured locally during the CAL project. The cost of ADF inhaled salbutamol was 1.54€, about 27% higher than that of inhaled salbutamol procured locally during the CAL project (Table 2). With an average of 10% margin, the selling price was 1.98€ for inhaled beclometasone and 1.68€ for inhaled salbutamol in the ADF pilot project. ", "with The Union consultants, decided to impose a markup of 0.30€ per inhaler as a site margin in order to standardise the selling price of inhalers and to maintain the services of follow-up at no cost to patients at all sites. ", "Medicine management tool ", "A medicine management tool using Microsoft Excel has been developed for the management of asthma inhalers. It was used periodically to assess number of inhalers in stock at the beginning of a period; number of inhalers ordered during that period; number of inhalers in stock at the end of the period; number of inhalers used during the period; average monthly consumption of inhalers; number of months that inhalers in stock can cover. This information was then used to estimate the date for placing the next order of inhalers, aiming to order 8 months before the inhalers would run out (a two-month buffer plus six months as the estimated interval between placing an order to receiving the medicines). ", "Evaluation of the RDF ", "To evaluate the RDF in Benin, we reviewed the costs of procuring the asthma medicines, the price at which medicines were sold to patients, costs for procuring other elements related to the management of asthma (peak flow meters, mouthpieces, printing of asthma treatment cards and registers), the revenue generated by selling medicines to patients, and the balance of capital as of 31 January 2013. We assessed the performance of the medicine management tool and check whether there was interriuption of essential asthma medicine at projct sites. ", "The asthma projects focused on long-term management of patients with persistent asthma. The second edition [16] of The Union’s guide for standard case management of asthma was used in the CAL project; the third edition ", null, "Note: CAL, comprehensive approach to lung health project; CAME, central pharmacy for essential medicines of Benin. " ]

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[ "Table 3 Asthma revolving drug fund expenditure for medicines and other items related to asthma management, Benin 2008–2013 ", "and mouthpieces through the ADF, and printing asthma posters, asthma treatment cards and registers. The total expenditure of the RDF was 29,225€ (Table 3). ", "Table 4 shows the number of inhalers to be sold and selling price per inhaler. Complete collection of money from the sale of these inhalers would generate 50,474€ for the RDF. Table 5 shows that a total of 32,211€ has been recovered so far from selling inhalers to patients. The value of the inhalers in stock was equivalent to 12,172€. The value of inhalers that were expired or provided to the poorest patients free-of-charge amounted to 6,091€. ", "Table 6 shows that the capital of the RDF as of 31 January 2013, including the deposit in the RDF bank account (8,114€) and the value of inhalers in stock (12,172€), was equivalent to 20,586€, which was less than 24,101€, the total amount of capital initially injected into the RDF. The decrease in the RDF was mainly because a number of inhalers were expired or provided free-of-charge (6,091€) and because part of the fund was used to procure other items required for the management of asthma patients (4,338€). ", "Estimations for the next order ", "Table 7 shows the use of the tool on 31 January 2013, which estimated that the date for placing the next order of inhalers would be in July 2013. Consequently, the NTP Benin sent an order to ADF in July 2013 to prevent interruption of supply. ", "The assessment found that there was no interruption of supply of asthma medicines from 2008–2013 in asthma pilot sites in Benin. ", "Table 2 Purchase price, freight fee, margin and selling price for inhaled beclometasone and inhaled salbutamol in a comprehensive approach to lung health project and an asthma drug facility pilot project in Benin ", null, "Note: CAL, comprehensive approach to lung health project; CAME, central pharmacy for essential medicines of Benin. ", "Expenditure and recovery of the Revolving Drug Fund as of January 2013 ", "Between 2008 to 2013, the Benin NTP placed three orders for a total of 7,386 inhaled beclometasone and four orders for a total of 8,865 inhaled salbutamol with an expenditure of 24,887€ through the ADF. In addition, the Benin NTP spent 4,338€ procuring peak flow meters ", null ]

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[ "Table 4 Number of inhalers to be sold, selling price per inhaler and money to be recovered for asthma revolving drug fund in Benin by 31 January 2013 ", null, "Note: CAL, comprehensive approach to lung health project; ADF, Asthma Drug Facility. *Includes 2500 donated by the ADF and 7386 procured through the ADF. †Includes 2000 donated by the ADF and 8865 procured through the ADF. ", "Asthma patient management ", "The results of asthma management during the CAL project have been reported [11]. Since the beginning of the ADF pilot project in April 2010, asthma management has been performed consistently and quarterly reports sent to The Union during the three years of the project. The number of patients with persistent asthma newly registered was 204 in the first project year (April 2010-March ", "Table 5 Funds recovered by the asthma revolving drug fund in Benin by 31 January 2013 ", null, "Note: CAL, comprehensive approach to lung health project; ADF, Asthma Drug Facility. ", "Table 6 Capital of asthma revolving drug fund in Benin, as of January 2013 ", null, "*See Table 5, money already recovered. †See Table 3, total expenditure. ‡See Table 5, ADF inhalers in stock. ", "2011). It increased to 231 in the second year (April 2011March 2012) and to 274 in the third year (April 2012March 2013). In addition to the 709 newly registered cases with persistent asthma, patients with intermittent asthma and patients registered prior to the ADF pilot project were also treated with medicines provided through the ADF. ", "Discussion ", "international asthma guidelines, Before the asthma pilot project, only a small minority of asthma patients were prescribed with ICS in Benin [12]. The CAL asthma pilot project began with national adaption of followed by training of clinicians for guideline implementation. To ensure sustainability of the long-term management of asthma, an uninterrupted supply of ICS is essential, for which a RDF of asthma was established in Benin. The RDF provided ICS at affordable prices for the majority of asthma patients. For a small minority of poor asthma patients who could not afford to pay, the ICS were provided at no cost. ", "Since the beginning of the asthma project in 2008, long-term management of asthma using ICS has reduced suffering and improved the quality of life of asthma patients. The proportion of asthma patients who had at least one visit to emergency services in the previous year for an asthma attack was 59.4% before the project, which reduced to 1.6% after the project [12]. ", "Since the establishment of the RDF, the capital of the fund was always sufficient to ensure uninterrupted supply of asthma medicines in the five pilot sites. Management of patients with persistent asthma using ICS has became routine practice in the pilot sites. The tool for managing medicine ordering was useful as it estimated the number of months covered by inhalers in stock and the approximate date when the next medicine order should be placed. The tool did not use the number of asthma patients to estimate consumption because the severity of asthma may vary over time and patients may not follow advice to continue treatment when their asthma is under control. If the RDF is maintained properly, it might " ]

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[ "On the top right of this page, is there a table?", "On the top right of this page, is there a table?", "On the top right of this page, is there a table?", "When you check the left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "Is there any table on the top of this page?", "Is there any table on the bottom left of this page?", "Is there any table on the bottom left of this page?", "Is there any table on the bottom left of this page?", "Is there any table on the bottom of this page?", "Can you find any table on the right of this page?", "On the top right of this page, is there a table?", "On the top right of this page, is there a table?", "On the top right of this page, is there a table?", "When you check the left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "Is there any table on the top of this page?", "Is there any table on the bottom left of this page?", "Is there any table on the bottom left of this page?", "Is there any table on the bottom left of this page?", "Is there any table on the bottom of this page?", "Can you find any table on the right of this page?", "Can you find any figure on the bottom right of this page?", "How many tables in this page?", "Can you find 3 table in the page?", "Can you find a table in this page?" ]

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[ "Table 7 Estimation of the date for placing the next order of asthma inhalers, revolving drug fund, Benin, 31 January 2013 ", null, "*Ordering must be started as soon as the number of inhalers in stock is sufficient for only 8 months: 2 months for reserve stock and 6 months as turnaround time between ordering and arrival of inhalers. " ]

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[ "Competing interests ", "Authors’ contributions ", "GA, NAK, MG, CP, KB, NB, DAE, CYC designed the study. GA, NAK, MG, LT, WB collected data. GA, NAK, MG, CP, KB, NB, DAE, CYC interpreted findings. GA, NAK, CYC wrote the first draft of the manuscript. All authors contributed to the revision of the manuscript and gave approval to the final version of the manuscript. ", "Acknowledgements ", "Authors wish to thank Cécile Macé who participated in the establishment of the revolving drug fund, Gabriel Ade and Ferdinand Kassa who managed asthma patients, and Angelo Makpenon who helped data collection. The study was funded by the International Union Against Tuberculosis and Lung Disease. ", "Author details ", "1Centre National Hospitalier de Pneumo phtisiolologie, Cotonou, Bénin. 2International Union Against Tuberculosis and Lung Disease, 68, boulevard Saint-Michel, 75006 Paris, France. 3Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. 4Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. ", "Received: 20 November 2014 Accepted: 17 March 2015 ", "References ", "et al. Promotion of access to essential medicines for non-communicable diseases: practical implications of the UN political declaration. Lancet. 2013;381:680–9. Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: a secondary analysis. Lancet. 2009;373:240–9. Babar ZU, Lessing C, Mace C, Bissell K. The availability, pricing and affordability of three essential asthma medicines in 52 low- and middle-income countries. Pharmacoeconomics. 2013;31:1063–82. Aït-Khaled N, Auregan G, Bencharif N, Mady Camara L, Dagli E, Djankine K, et al. Affordability of inhaled corticosteroids as a potential barrier to treatment of asthma in some developing countries. Int J Tuberc Lung Dis. 2000;4:268–71. Aït-Khaled N, Enarson DA, Bissell K, Billo NE. Access to inhaled corticosteroids is key to improving quality of care for asthma in developing countries. Allergy. 2007;62:230–6. Burney P, Potts J, Aït-Khaled N, Sepulveda RMD, Zidouni N, Benali R, et al. A multinational study of treatment failures in asthma management. Int J Tuberc Lung Dis. 2008;12:13–8. The Global Asthma Report 2011. Paris, France: The International Union Against Tuberculosis and Lung Disease; 2011. 8. Murakami H, Phommasack B, Oula R, Sinxomphou S. Revolving drug funds at front-line health facilities in Vientiane, Lao PDR. Health Policy Plan. 2001;16:98–106. Umenai T, Narula IS. Revolving drug funds in Asia and Latin America. Lancet. 1996;347:1698–9. 10. Umenai T, Narula IS. Revolving drug funds: a step towards health security. Bull World Health Organ. 1999;77:167–71. 11. Ali GKM. How to establish a successful revolving drug fund: the experience of Khartoum state in the Sudan. Bull World Health Organ. 2009;87:139–42. 12. Ade G, Gninafon M, Tawo L, Aït-Khaled N, Enarson DA, Chiang C-Y. Management 13. of asthma in Benin: the challenge of loss to follow-up. Public Health Action. 2013;3:76–80. Kan XH, Chiang C-Y, Enarson DA, Rao HL, Chen Q, Aït-Khaled N, et al. Asthma as a hidden disease in rural China: opportunities and challenges of standard case management. Public Health Action. 2012;2:87–91. 14. Billo NE. Asthma drug facility: from concept to reality. Int J Tuberc Lung Dis. 2006;10:709. 15. Billo NE. Good news: asthma medicines for all. Int J Tuberc Lung Dis. 2010;14:524. 16. Aït-Khaled N, Enarson DA. Management of asthma in adults. A guide to ", "be possible to extend the management of asthma to other sites using medicines provided by the RDF. ", "Several challenges should be highlighted. First, the government’s political commitment for national asthma control was not yet in place and funding for the management of non-communicable diseases was lacking. It is challenging to ensure sustainibility of the long-term management of asthma. Second, maintaining a private bank account for the RDF in a public health structure and keeping the health personnel motivated to manage the distribution of medicines and the replenishment of stock with monies collected from the sale of medicines over a prolonged period of time might be challenging. Several issues arose during project implementation, such as expiry of medicines, money from medicine sales not recovered, medicines provided for free but not recorded, and money from medicine sales recovered but not registered. Consequently, the capital of the RDF was not fully recovered, resulting in a decrease of capital after five years of operation. ", "The Pan American Health Organization (PAHO) has established the PAHO Strategic Fund to assist PAHO member states in the procurement of essential medicines and basic public health products [18]. In 2013, PAHO started to add medicines for Non-Communicable Diseases (NCD) to this fund. However, there is no such regional procurement mechanism in place in Africa. The World Health Organization (WHO) has been advocating for universal health coverage to ensure access to health care, for which countries must raise sufficient funds, reduce the reliance on direct payments to finance services, and improve efficiency and equity [19]. Furthermore, the WHO Global Action Plan for Prevention and Control of NCD 2013–2020 has set the target of “80% availability of the affordable basic technologies and essential medicines” [20]. This target applies to asthma inhalers. Until universal health coverage is implemented and providing access to care for asthma patient in Benin, the RDF will continue playing an important role in ensuring an uninterrupted supply of essential asthma medicines. ", "Conclusion ", "The Benin experience demonstrated that in countries where universal health coverage was not yet in place, establishment of a RDF may help maintain an uninterrupted supply of essential medicines. ", "Abbreviations ", "ADF: Asthma Drug Facility; CAL: Comprehensive approach to lung health; CAME: Central pharmacy for essential medicines; CFC: Chlorofluorocarbons; CNHP: Centre national hospitalier de pneumophtisiologie; ICS: Inhaled corticosteroid; HFA: Hydrofluoroalkanes; NCD: Non-Communicable Diseases; NTP: National tuberculosis programme; PAHO: Pan American Health Organization; RDF: Revolving drug fund; The Union: International Union Against Tuberculosis and Lung Disease; WHO: World Health Organization. ", "The authors declare that they have no competing interests. " ]

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[ " New Medium for Pharmaceutical Grade Arthrospira", " Amro_ Amaru Alexander Steinbichel? Wud", " DJcpur Irnent ef Pruratn Reseurah, Genati EnginexrInz Kict(hrunrh Rcewdh Jrastirutt; (Mcat ACt Screrilin Hcst AMa Teclnolg Apclicalias;, Umilersilis Resturdi Celtre Disvich Nea Bor E Arck PO Bux 2[954, AluxldraLevnt \"aeriria Muaur ' MICTz4WubI Ieuterhaxoplc; Wetlulser} IWlcItac-Umarar Mutste! ( urnnehal4, Aehu Mwosrs Gernim", " Academic Editor: Gary Dwke:", " Cumtgnt AMA Stcmbuchcl ACo~ ankk:diqiitatad Ulcc CicJiler Culnols Allribuliun which Ermils unnexricled use, disIribulion.and jepruuuclion inan mntlium; pruniued tha urieinal wurk is nmonerh' filed ctte ", " \"pcnim Oliasadi pharmaceutical Frade sinple productol -nuosalr tromi mued rultun Ye nave desiEned 4 Mccietu dctfenl [toaut $ cointi-Ilot bctwcu Gcuert atd Latouk malls ncw Iticdiutt /14> Ue aeillgy t0 aniedr diflctent Lums ul &unobucterum and mictul Extepl Iha Cilunluu. Tne niedium Jnu tla cultin Jtion cundiliors har peen investiJed nwni onk Aracnira cnuld Nurvlve For thar mlxey cultut? M Chle Anrrit AM)has ME UA Gsn ncWT chnatentnal chmenl uL te Arlnnjini SrnIh einhibilinn Mae Ar aenahlchcrctennral Incnldu Photabmnte-CET henMeid ILUhlzh dine (LLA-Sl} medium #nich [ullowcu mc\"lur reUucin\" cuncenlrtion lu|5 Ikt inrstiealion puyes thal Cllan!h has comnletelv deacneared mnetho #Sw An Mamm ha Nen #uhlih lng nhatabloneAnorIor nnucn single ccll Arekespire. Suzh method cnables the praduztkn & pure pharmaccutk:l grad t[TeataMI Tedicn Lard phamiceut-cu apolication s 3sncle prOteIn ann wmwh EnItIA Dezn", " Introduction", " Using agac mcdicinc dccns rputed utnal aenm ECYpC A0 uuh Maclem ccllert Jgnc on ShTMC Tuicr comicatic narale cnuoncnt Wncn Ic Jnd Mun CuCcO Fue Allit significant Acmat Sourcr Tha alkaline lakes cnablc thc uocth ol onc 0 thc [cw nontoxlc cwal obactcrial snecic Arutrosrint Haoriu Fumans eatner rirthnosoi Gourcr [nierant Lrds Slely Arhs:Dta Lllel (amingoes (Phocnicaaias pinor Geoffroy) enccurlges such Kcheda (7i TcDonce Ethlcnia Farmcre and herSmcn MFUL 4e4s clus [HC >udi likes #IakC catte drink /athrasoir Watcr aboutonce nonth pdlcve chatuhae thcran \"Utc chcand Comncne tcs omaAc dietar : fod (2. Huc Ioxirz Ercing", " Una invention the mcrosconc enb?dJutnin Mdentin aud Lescril Anrusnra Spr C AOEACICILI", " 13]. Speries Atutnsria HivL heen Iound VNeli cnuronmcnbs Including Sll; sand manshcs brackish watcr Rum Uluai[ 4]. Rich tepurted ominannavonincmn numher Wallcy East Africa \"can: Jhcr Its hrst Mictntcopic {denlifcatinn Aethrustr Tantraduced tns wotia Dangeard (1940} from Amnia collected by LcACL pHzHIACLS MiuIkel Yu Arinaullra cantiina hilt letel 0 ntolyins {50/07 Lipids (7-16\"} vitamins and Omcza fatty 17-9|. For LCOnUIHLC Fuduclon Anlhou_Dirte IIS USU:IN culu;Aed nch ponoe Absomed LuciL fix inorganic Katnon AH{Dirt produccL quantlic exceeding m on Teal miienii [1o]: Suryet conaetning production Shimamatsu (2004) highlighted FMmIamT ulmer EE_ JFCLLS miin nrohlem: conceming its prodluctiaxn tkeoten ponds anaksis natuta habitat cnbicd Larroux Ayhhi lce ic usAlir Iedmi Ml Aur nver #cientiat hve opsenved pecaeIne most (19I1)" ]

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[ null, " FIGURE ]: Npeht protle 4 tc pholcblotcactot cowing Ulc Ilntavdciti Ib} Dczasduechalttr7 Jnd Ita suitlcse Hcc] cuectwlich containa ditlerent ports and gowth mentanng probes (2 $- PH meter; CO;40 electrodeztemperrur and aple callectian port} (c) Lxht erwth oftha Arhrasnua 1fter the medlum dilutlon (d) Hewy Erwth ofthe aNoltha cultavatlon nrocets (aSurla cullivalion 0L Alnhny\"Ini uyessun ligh only_", " nuan IeTl stetilzer sniniel; Un picleria menbrnehieri0 22am ) For Toutinc cultivatian; light from GtesCent [amplsunlieht td (emnperlute (fetS Iturn 20 uneer Aanccaneaan Lene Veed", " Kol Lutatiod: buttlc [ne _mnenum trom the photnhiomactor duting thedilution ntOCES Theremoted \"dium admneedto 5xandthe Anhou_Dird #usaluwsed eoi\" lnder sualic cutdiiun SamJe iLs Apnve)trun Me", " Kulubluretlctor SterilzWlun drel € dtovalJon eLint", " Kulubluretlctor SterilzWlun drel € dtovalJon Teniirs photohiore actor; except Jight paneks mator_ stcrilizcd Tap WA(C contalnng part A-St uedlurte UNL IIULL 6612-[ E CIDci auto-lave MLS steriaation Umkh Ukching Ucman; Part aicilized scpartcli MSnS Auruc hucterial membrine filler (012tn ) Ihe ial tolumc rnz Mediuni constimuents hna bccn maot addro eLint Aling", " seninie Ine Molobiceilctom jonieve Fce Unme of 70L Pant = which contains the yeast extricUprptone aulaclved using #Otnal aulaclve clecttades and the cenmicMer: WCTL {Letized *piniel", " Ctu Cadditiart Thc photobiorcactor chahled uuomalic control; The temperitune Z0 ( ind Wils auiuscd JulOmlicilly_ Ie suter sred ( mnolor seed) pH WCIL monitoted Jutomatcally: The r parmetets At the starting [int wcr pH 9.11, pO} temocratute 1 and OdaEm cmnles WeraMken and wnenevt Possible \"preu orm nzulatk", " 2,9 Cell Dry Weizht (CDW) CDW was Fakculatenhr cor- relating wcight volumic Futct papers juzc boin Tcrc Uscd The papcr or gauze WJs wclehedbeforc bcing uscdand dricdatter nltration; and Ithe weight correlated to the Fulul CDW" ]

[ "5", "1", "1", "1", "2", "1", "1", "1", "1" ]

[ "Is there any figure on the top of this page?", "Is there any figure on the top of this page?", "How many figures in this page?", "Is there only 1 table in this page?", "Is there only 1 figure in this page?", "Confirm if there are 3 table in this page.", "Are there any figure this page?", "Can you find a table in this page?" ]

[ "True", "True", "1", "True", "True", "False", "True", "False" ]

[ "existence", "existence", "counting", "existence", "existence", "existence", "existence", "existence" ]

[ null, " FATTAT Th ovcrall <ukivstkon proxess Using photobioresctor Thc heary green |ix", " Mcuscoplc Examllation Smplcs Wcre drwmitom thc polODTEAc[Ul rexuiny AIC Jenga Fossible ud eximined Iinz lian: micnecote_", " CUMnM Ne telma Compusstion ALM cunpitisun stud; Wra dor hetween the Jileren: used media LTdCT stand Inclr dilicIcnt cicct Artwespin bascd MealanAmin fAmMAu Doath", " 212. Aatlrosplra Toral Blowlass Collection: FOT collectne thc Lurtilss Aeo Man Ghraur peffotmed Using spong? coveted wnith gauze", " 213. Berlass Arthruspira Liottas Jued MTAT 4ptk candmian: Paseng tetile Arha nira bjomaSs stcruc ncroblal culuvaton cibinct_ Dn ig", " Results and Discussions", " Durin Lestini mnedin cnmnaition ILn? Cnlarlla ad Arthrospim Iboth Iolaicd bv mcthods oincr than mcda KMeWem Mm FEt_ ulei Unicentner Adata showni chscnrc high amount Na-CU (27 wtv) cnabics Acturosou Jd en Iourish but inhihils urnsth otntherilal Mht Gfen rirthnosoi Mnerm AuaiTonnic candilicn Icd [ peplane easl extrucland tAp Wilct Hnee Thritic Lemeni< mixunra We hare selected the comnoncng mcaum from both Gconges and Zauouk s media.Gectges #ledilm 4LUIMIU [edium [Ol algae cultivation Gcorees mcdium Eeptoncand thc Nalr gradients. Thc constituents which {trouk medium have heen selecied hilser selectivc mcdium tor the Artrospira. By accident; conraint betb =", " 4 double concentration (Zx) of 4-St medium The Zx medium UTon usedouud all tke Chlorelka Fot [nat # develaner Twrt slep strateg): firt using Zx medium cfadlcatc Cullarella and thcn dilutinz thc * mcdlum t0 LSx [HzI AMI:CIt C [ MNS AKalL \"Tbl -3}. We used light microscope ualuate the Dmfec Showed thnt afcr 2 davs or cultivation Cillutella wascomclcic y cradlcatcd Moreovet Aethrustru *unvveD Antar Mdnum Ihnui (ns vcas erncUnenton MtFe This initiated the idea establsh ktricutu purilcaljur Anthrusnin eav- onaminalem Chlonut ( Arthroshtru ; ArE (Figures I(a), I(b}, I(c) Kd), and I(c)). The cell dry wright (CDW) Annrusnin 4-82x Ald LSx medb L plulled Iinean exnanen nil scile Nzutes other parameters have bcen plotted against time In Flgurc\"", " cur;e Aathrosoiru Fepnacnts tPical GTOwtn M TOEMcmnt anote ind fatinniti nhix (Figure _ The total ~ield a Arlhmshira biomass CD 09/4@L 04,,2/0 Fhown Figure uwle Aas:Dird aeau i; still <imilar the micmhial gmowth curvc FieC The calculated cuductvty Xsan){tena Len the CDW gL naini; nA the timcs and cnd roints FOr culutaton USg tnc emM 0muui3 (Lic cculed >-Cnc growtn x) , M#aeh ano (nc calculaicd ucncfatuon (Inic 2/4; _ Sliin ciluing medmmcnncenimhonM Srasin Figures 3and the abore values Javc Kecn increased ~significantly; Wnem 0.003 gLk uuil gh 17-6s_ significanf increasein anetin Ithe decesse in 4 aenedium Dmovathatealinin- Gecntialactorinthc glontn Dkal az at VLh" ]

[ "5", "1", "1", "1", "1", "1", "2", "1", "1", "1" ]

[ "What is the number of figures in this page?", "What is the number of tales in this page?", "Are there 1 figure in this page?", "Can you find 1 table in the page?", "Can 'background' be found in this page?", "Are there any figure this page?" ]

[ "1", "0", "True", "True", "False", "True" ]

[ "counting", "counting", "existence", "existence", "existence", "existence" ]

[ " MCAE Ch Ule Arllzrusural 4- 4mneuiun: Lug", null, " HGURE 5; Frta cunee utthc CD \" aLalne[ OU-_", " j0l cach ol 4 ud I3xhavc bccn calculatcd FlcF MIIun cach stattntg' poit We selected tha best fitted points ctponentn CF mcdium cultivation Fcurc tollowinc eauatinn: cultivit1on Ine #arling nane poinu)K Mhandinerno naint ie Ioah wmikeIor /7cultivation thc TInt Gull6u hind the etd puint [ ATi_ 2ronth", " e Tettesentali Tina hnth culntatnniehiu been calculated from thc following formula:", " Bcih the Ix and LSx sopes have peen #electec |rn matching points &5 in Figures Whci Pointi) 4AMnA Uls culiSton respeclitel puna", " Analvsis ofinc @Vc mcdla usu cummJZcd M Taclc [ eSmAMA Meut Haii RaeUM calcatro Mol l medium Conccnirauon similar Lanouk ; mculu Trh nedjum coniams high imount ats AS5m dium Idlcaled ke middle heeen and hoth ora-shrland Zarmul; medium_anaj G4v2 tke best tesult_ Ile ardtess ul euch mediuni Has Dcen ccnendemm F fallcwing; formula;", null, " FIGURE 3; LOg CDW UAcmOtTA Mue Metnundesn mru", null, " Arthrospira enrichment: The increase of thcP; His PLEn cilcululed fum Ie [OHMZ: and Tullo~LE", " where X is cither Por 4 OT g", " Theclculuted Pincrenit Foncren 83\"u ind", " ie dllictn[ med: used extepl Geurue s medLum Uatlc 2 nc incredSt and Agionskads t0 Incia M Mnanat There FCTC relaticn`hip hetween (Jlorella inO Arthroshiru dinerent alt concentrations where CWona dcTeasc$" ]

[ "1", "5", "1", "1", "1", "1", "1", "5", "1", "5", "1", "1", "1", "1" ]

[ "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "Is there any figure on the top left of this page?", "Is there any figure on the top left of this page?", "Is there any figure on the top left of this page?", "Can you find any figure on the top of this page?", "Can you find any figure on the left of this page?", "Is there any figure on the right of this page?", "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "Is there any figure on the top left of this page?", "Is there any figure on the top left of this page?", "Is there any figure on the top left of this page?", "Can you find any figure on the top of this page?", "Can you find any figure on the left of this page?", "Is there any figure on the right of this page?", "When you check this page, how many figures are in this page?", "Is there only 3 figure in this page?", "Is there only 3 table in this page?", "Is there a figure in this page?" ]

[ "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "3", "True", "True", "True" ]

[ "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "counting", "existence", "existence", "existence" ]

[ " 1 ", null ]

[ "1", "4" ]

[ "When you check the bottom right of this page, can you find any figure?", "What is the number of tales in this page?", "How many figures in this page?", "Is there only 1 table in this page?", "Is there only 1 figure in this page?", "Can you find 2 table in the page?", "Can you find a figure in this page?", "When you check this page, can you find any table?" ]

[ "False", "1", "0", "True", "True", "False", "False", "True" ]

[ "existence", "counting", "counting", "existence", "existence", "existence", "existence", "existence" ]

[ " AALT Aueer hardneenahr Mncren medln", null, " Fe-LmI Theelect Cc the JCht BuhFU CDYVL", " with increasing sle conceniTitinn ind Aathrasoir Fablc The relationship Dtwren Arnrenot CDW McE An FXUILS ind5; thiti the Arthraspira ( VWY causes LCTClic Dillerent Ieht intensities; including a Rne A M An ricue AalM Scnsinycornoniorin the ctect ot light in the cutvaticn plulls> thc IJp log phase; the chanec Intensin- not cleiny Eetecled excepl [ea minks 3ohk This nccauS the Ing phase cell iLd @LIUH Ter ' sluw and (Hle lon phase the V ite Yen high: Tne chinge coulannl detected cleitly Rth umieth nnae natr etatonar Dfns wherethc gmwth DccUms mure Hubl CUNstAl ,the elect hiLs Ucen clezny nhset ed anddhcved tnatthecectezsein light inlensin ledto lcncac gowte thcanount ofthc reeascd FICMC gotth", " ArMusdira can harsh conditions, and hiormediatio oftecic dcmcnte cck lcidand ntnertoxic elemenks and ccni\"unds [3, 32] Helerutnnhic mctabolisn asteT than autottophic SSil 4nne Chluala ueeuWueela Lal iicluded hish levels irilinit ; sinil aulotrophi granvtn Arlhniskira pfoycd surwvc thcic condltions Whuc Cherldidrol the phatabioteactor Mnocuna cirin cmte", " condilianahnt put Artirospia Clorala in cinected Me added %cast cxtacuncptone mixturc ahcr diuling [Je Je4luma 16 TeruMla LclGananed pH; Ws Aler Inoh himh conditions thc Zx A-St mcdiun thch dilutcd and tke Artkarusowa KtOwth satted aneaees hinmase Ghoyn Figures I(b ana Mc atcti", " Vcstoppcd prOccss ahcr Jbout 4 h aftcn (nt rateehi FCEAEl Increast piomas relatively equa thcincn4 PO_ (% = aaturaticn | Wca ~Jueical Fhle Ue elexalian Inaicatul KaGK nmith indmullinlication; pO,indphareneeativet aneced temnaramna Tce leads Ltcieiy Lie [ermnentalion ptuces [LIIeCalure Howerer [ne Tinle (the cnange the pH and imo Thc Wdden cnanzl mnini Mat thar thcrc direci ~liecl On (lc AtoUsDi PIUYl HYures MarameteTs 0 the zrout prtore ano thc mcdiun dilution pfOYc that LSx A-St medium hellen Ercnwing Artkrspira than 4 Y Medium Thiis another Pmof about the role ot elinity Ievel thc EToxth 0 CViobic[en Teteot Eac ama Hiretenlnedi whici Fve peen according keir Falion; ince saliniti Gnoum abic [. Accuromp dita In [ablc , Tible inn a IA Meal Enuntk nuUng" ]

[ "1", "5", "1", "1", "1", "1", "1" ]

[ "When you check the top of this page, can you find any figure?", "When you check the top of this page, can you find any figure?", "How many figures in this page?", "Can you find 1 table in the page?", "Does this page include 1 table?", "Can you find a 'conclusion' in this page?", "Is there any figure?" ]

[ "True", "True", "1", "True", "False", "False", "True" ]

[ "existence", "existence", "counting", "existence", "existence", "existence", "existence" ]

[ " AALT onktacs hnth ( Ainbplnt tetenemcdia", null, " which Ieads the eradicatiog ohtna Clonl On the other hand Acturosoi provc: noucnw stam (nat could FeS dtlert nial enecii Sulo", " nis sudy not mnvcstizatc condltlons Arh nira nverprk_ucton Jcl canshnis anilyes Yhlcp should royered tunture acic Howter cleary DIUYE Bl; CIL[ICL Menl; nfinininn ther 4xcies_ her Anhadira thoula Wcila ~hu-Cai snd; hccausc (mete eIcal \"iftabiliy the \"enulype Ad Ue Slile ulthe Many cther tactots| Icported by Rucngjitchatchawalya ctal (2002)(34].By mimickingits nat- utal hihitiE using the photobicreactor within fermentor nartal Nandoniztior its cultiwation condtions Eain 4 DELICI MUCISLAHOML Ar[MruspII HUwlhi cuni-uns. aouk. Bronth", " Conclusion", " In conclusion, slinity Wisthe major factor which leads dcinance (Artnrostrrherinan the alkalinity Purilying Arthnspira trom contaminated algac cach DMAFMace Lical LML 21/151 A-St medii inprove tne Artrrospint quality; Ip wicr and yeast exttilcV pcplone mixture can substitute the trace elements thc Anhudira COhietci prudLCLOM Ile tempcrlute Cuul <LC amount the PH value citner direc dilect mducig Chcmcan pnrscal changcs Ertkmira KLTL its envimnment Arthrushim h:s ntovc \" Mot? environnental; ndapted Cherl thieelud aucceede 4eeuT - HILEUJUI ind cullivalicn sondition: enih iniin ennchment Arm nira Inhbition cthcr spccic) ined Ra ME pLulublreuclur Ad Cunuuc nL conrici cullunlicn Dmcer Halionat: chasese prvcd chcien quickcst urderstand the diffetent [Espo1ses HFMEANAT ditferent odinications during cultivatinn fondinon: Tnis sud\" WlL opci thc Wa producc pufc cuturc Arnicra Kaanaa Mekha uelo Tlcluan Tozunniee Arhnkcira nroductian which adlects ins nronuc qualic Uur nEW mcllud J8 nul Expensfe reliable itd costellective Ate medlut ucr U Leen Itnm Ihe menMt luring dilution stcp dulned and lia Rrctcoi Arhtu:Dird Cil Fuduceu W MMOLL AMY HA cyinubic- conuaninant Ufs W ins production Arlkmraana cnables the Purification of & pfeviously pro- duceo coaminie Arutrosrim nhtained |rax nonds/ srdt change Hro- LA {m Emal", " Conflict of Interests", " Theauhors &eclare that there i; conllict oinen tS", " Acknowledgment", " Ihc aumon acowlcdec DIC EnS Hclocr Ancns tor somc [CCHC RUPTOH LL[IL LL wurk: [CT 4 ACAOW4LC grant provided from ine DAAD which SupPOrs pan (s stud;", " Kccrcnccs", " c4l Ke7isiul. T0.T.PP 551-5/8 1985 Khdt sranse ai Scunulilu nudtuscAmnkcn Jusi- Rotmri i cmg; Lqqiui < Juumt & Apclira Phvcolju Tol 4no 577t \"Turpin \"Spirulina oscillaricide, Jcetiae\" Mnf \"crnduny vol,sinp Juy iuimettal_Harecranic Ahn, and H M Oh Phrlo e netic relatinn Aathgujoth Hnnanceal Mrutnonae pcnead cpcha /G.*quences Aue,val %M_ Rick \" oter Antwocnira MAlatuske , Rel AWut_ 75-79,1931. Danpenn umeneITc Dur Fhomme Auleanira nlalcues(nda\" GurnuAr Actc Sug FctG Cto t Hl Chamoato UtJn Ur Litua Ataula Pda: Sallos Crballos;anu Casliliu Uudale WNunLculua Anulna 'Arnsnu al Artttk CatnncT TIS UnWrou *u FP.132 S Kchmnnd Lare emicrozlal cwlut Epoliation Merssin} Punelrica Rcsteitu Keptess Brisol UK Avila- Chuce Malnci M De Can ITAISA Kny Kilh Anthrospin3 prolein antinina content cultivaleu prores; uaing 40241 Dtort wulct lcure1u Arulicd Wic rubielogy; 1036-1094 Shlaaeu_ \" A AEet Soiculital Nibk micolE; Hunt '0llY4, \"LSZ Cud Zanouk; Lwitnblaa\"i 4T4ar dunz CvlcJun?1 ee' JrJle cr Wivets 'ucIclcs DIclc = (uimicucs ATOranit Nlutasvuttes Sclmulichu #hutbtiz Such Ganer Gukr Mll(ce IAUNa Katam KMn Holennc ellinice 2Iru jld Malers[ (Liom:) Ghl IcUptA)_ IL IUllre Kmcl Fnz 6Pn Laal" ]

[ "1", "4", "1", "1", "2", "1", "2", "1", "2", "1", "2", "3" ]

[ "Is there any table on the top of this page?", "Is there any table on the top of this page?", "How many tables can be found in this page?", "Are there 1 figure in this page?", "Does this page include 1 table?", "Is there any figure?", "When you check this page, can you find any table?" ]

[ "True", "True", "1", "True", "True", "False", "True" ]

[ "existence", "existence", "counting", "existence", "existence", "existence", "existence" ]

[ " eset Ms hmonstn Aacan mnarz Ghur; nlatl tIning, Lulan\" Frmu | AuraIx PIli Punt; > Runeiy Ed 113-153 Curieu [nslilulion Washinglun Washington. DC, USA. 1958 [0a] Y-A Lee and Rcl nhathionacoranclnelnn niomas nmocucttity tenor AL alture, HiuletIjlour Rwcugincerina 005_Mom PukAup Retspectises ofphototrophi< Ikcro- ertmnmer protection Ralop; Hralctneerica 517-520M9i Ahler Gmjentlo Sleinbuchel; Auenic cultivation of Aox}gcnic phototrophi< buctetus Cnenacn micnn new closeu lujular %ast Pholobioreaclor; Anaerd Micrabloles 'Btotechcsolasn 339 _o Oneel an4 Sukn Comcurkan oftwn didernt pnau- MuHecal: IniedcmAnninmecort Int MANnu preciei * Difea natioMais, Kauneeulaa hcla pR [755 LJen 7unr [LS] M Maksuda Hiezema Converti La ~Plaxenvtthcti Kaata Amn Aeelmnlalnn Arilrospud (cruitlu nareE cantnunual culuvala tUbulat phurcbluteaclut . Kiulateuaduux Yuuttti_ HZ HZ, 20l2 NirAlmha Venkatarama Eesum _ cae Iht blur-Sttn 1y Seuuiru MAlrlSs (cItkt; DlrMal unnfwnerAil Qu A4rlcuture Play; Kin ana Ota \" Solrulla ( Anlinbaoltl k. notentlal applt Wion Lunal keed supolenienl; Ao\"ic Hnlralak! EM4Y Ottcea-Caho_ Aauclos_ Hctmsu; Am ~menei Chemc CMILDOSAD Spanira 4nd cukrvotic proucte ItatkcIcd Shalm' HcolT U5y HItJia Ianaka Ul launOtIIUt J Sakizuchi 'Artinxidan: activicie: Fhvcoc Lobjin prpured from Solrulit pltensts Annlicd Phprology, Il: 12 FJJ Sh Me Irom _elrulilu, Nrm Fuud Mdlirh: val_ 1-2L,[991_ T KuraanAnd ? Alheric \"Phacevnt heticunit oreanizat Mt Flut FhyslaJr. TU ndrirucienancher Hutton Usecm Hctlacz-Gicia Calt-EAItUpJ ~Phyccbllipuscin: Jcihnime Arllzruspiza (Spirllila | n4ima Gata t AplST HgC1(z}-causcv MnH en Qaltuge, Fom LiemmfifTolL Masui Shara AmAa Aboul-EutcIn dal, \"Murcul:i Julct Licalion chaructttiralion utht anliherrei # Inily ol Ule cimabncictilm An fusfomllx\" hlzie S= naM Hahi; HFLh , Alednand Roilma, LTWA ahibalor enveloped *irus nplicalion Pluc-zmeen Az Solrulba eltenst' 4Narlrd Predscta G5ann Kanr 'Char UR enla 4rn4em Dulr- Cnat A Rumeni 4ilcm LT Thiy Luela", " 4aimme FP.488-493 phatachemisty salc sttess ths canenactsetium Scnullcuul Mdicai Wuurul V Exeriric\"ut 411-417, Wullu MMatam Fads rencruataecu Poca Rnon Fl Usa ainn_I57 Cnen unu Biontmedialiun polenliul uepirulina: toxicit: Jnd bicsorptan studies bunia Zltejiang Voirtsty F' [71-174, 2lo; Rotinski Chcrrukhina nnnchenkn ~Ellect pIlc cohalt *u blckzicall; aclve Sud- sande contentin spirulinabiomiss Ukniis\" Fiokhimliclavi Zhutallvul PP 112 Mtco Rinagh Duiin LnYErI Dal Borghi \"nicrat? And nhnnhale Temalny * ?IreIuMuplul Hz4s , Wuunull utnlduxtriui Micrciulon- Bioletlialor= holl; 2(un Ruteciuchalchaw Lya Chictinan Chikakan Hunnic antchamen IXahnum \"Pnotosnthatle chutaclctiJlon 4 4 mnurant ul Solr \"inaplwit*50A Ctaal Apcrd RaicoleYolM KALIA ~Feinondt Mar Net" ]

[ "3", "3" ]

[ "Is there a 'abstract' in this page?" ]

[ "False" ]

[ "existence" ]

[ null ]

[ "5" ]

[ "How many figures in this page?", "Confirm if there are 1 table in this page.", "Does this page include 1 figure?", "Is there a figure in this page?" ]

[ "1", "True", "True", "True" ]

[ "counting", "existence", "existence", "existence" ]

[ " Anxiety and Anger Symptoms in Hwabyung Patients Improved More following 4 Weeks of the Emotional Freedom Technique Program Compared to the Progressive Muscle Relaxation Program: Randomized Controlled Trial", " Jin Woo Suh; Chung, Young Kim; Hwnn Lec; Jong Woo Kim\" Fong Sang Jung", " \"Sungmo-malkm Orknfal Clinic , 239-53 Muk-dunz; Jungrrg tMeni Rcpuhlic ur kureH ~ xhar} Gurz lurz Krung Hcxr Universi) Hosnifhl 1+730ngt-Dun Lhl\" unip Ca Ralb \"Hertllciet > (Jrleutal GMlc217 *Mu-d Ganguk:-gu Sequl !42-8X6, RepuNic of Kona", " cadcunic Fdico Michoulat", " CoiTitht 20I5 Iun Wao Suh ealThis Lrticle ditribued under Creali Comn Atrijulinn Licenx nhekicttut _ Mcu Hiatlhute Atacnoduatlan cdiuti tttid thc igia] woak Annannculcu", " Fox7oun_ Ibm ntona Hercnm [echn-Quc {EFIJ Meticunenad pschuogra Mherpr: Ik cenica eeceuealee cllectherulees OL EFI 4 4 ucwe (rcatitictt Ukkn [ut Hwrabr ung (HKAeaticnt exectctcIng anpct and €utpates tIn eticac' Progressive Relaxalicn (PHRI 'nana edilirian techn Wlal: Tne EFT and przressn € We apekhctthad Nehr= HkeCnIAthncnacitice Alltt ale AtntIct Al5t atlutmnmi kalu: und prustln Eue chndluced TlenlInen cumnied *l-Inaining prUSTal Gcres eontn ehinn A Fhcnaeuns FFIZup experienced A slgnificant decrase in the HA MPIOIE Anect stale unu paranwix idraliun enlin interiu theie Wrre sieniltJl Urre*tsin Gumplom #cile anxlety aneer cAnefr anxiet, hortilmt , and on In FFT grp U.is)- enalnuamou EFL goup tnoued unpuYeU pechulusical *\"nRomns nva symiploms graler thal Inuse Worened th? PAk Zroun FFme eilectively Alevxed HkS mroma comnareu PApAP Houp shancdpetter manlenance dunng x-Inining sucuestin \"uuu mnudel ol sll-cunuu Ireulmnenl in HB palitnes_ Neteht Nurk Vulur 0 7r", " Buckground", " Hwibyung aa aaluri Kue descnhec the Gosary Culture Round S ndtome Diagnotic and Statistical Manualof Mental Disorders fourth editon (DSM-Nv Appendix Khlp Fua: HIYCI d Cean AaM ATEer syndmme HR patients experience chtonic sufpressed Wllci Lpicsyumqut >bIUIS icudinz [cclings Mesi Subiec(ive iLLCI LIIcMEL WLLC WC cenaauan nushing cheat dry mouth, and sighing and PSy - cnclogical Smniom Icclings unfalincse ceenmueni (2]. HB s tepxtted A4\" of the KoIean Geterl nopulation renuen -incoma middle- oldcr housewives (3] suudlcs investigating", " MenenGNGIEDU nonpharmacolusk treattnent [CCCIYML nncnuor Terntch ar", " Progressive muscle relaxation (PMR) Widcl; relaxalion Lechniquc iTmhced Kacnhsnn reduce residual tension And ultimately achisre [qesha d (luruush pluxreSlve #IUCEss ul Inusce relaxioI enneon prizresve Musce mlatiltinn modelsanricinily dcsigncd Tclax ancuximalely MmSE; Mc ctended mure Widcl; Mscd muscle rltaliul technique devcope_ ernNel comncarative % Jmn 4 rCLAXnL mueclec 4. PMR can decreas Phyusolog MiIE iid JEin ucceleraon uolul DANaSYII athetIC actinon TIhis mcchanism thc 64-78 rvidcnc tor Is Mmn hcndids PrcvcntOn Cance prevention; and rehipiliticn (onventionie Audies netn Lm*7 hrce Panud" ]

[ "2", "1", "1", "1", "1", "1", "2", "1", "1", "1" ]

[ "When you check the bottom right of this page, can you find any table?", "Can you find 2 figure in the page?", "Is there a table in this page?" ]

[ "False", "False", "False" ]

[ "existence", "existence", "existence" ]

[ " FMK reduces CECL phrsiczl SHPLUIS SLEIHIIS sc\"cral pscholozical discaics PMR has otm dccreaseantiel;\" jx especially elc Fclucins ITOm dcpaon nnxiat ederly Patients, pTeventing both alfective and bchavioral disorders PMR also reduce antiel; and psychological Lidress shile imciovin suhieclive well being patient;unth -chixnphreniz ilsu KdWI reduce Leatt IAte #nd bloud ptessure [7]. PMR cuMTenu; Mnlzen Datients studiae cunductcd supporung Wuccr", " The Emntinnal Freedam \"Technique (FT)is Mendin 6asc, na;cholcpical Incrany that Allcvtates naychola pIc ano Ausumaal conblaus LPLIL LApPS NILLZMGE Cenamt meridin acupninl Lechniquc uilize cncthcran; icchniqucs such aeoulnet shilc accline [HPpIIA SLLILLAMOI UHlU ucupUnts Tedear eutnulaton (icdheart petiornec merician Tannins (henty cilled cmctional icupunciurc houht Therapy (TFTV WJs Mucnaiaeu Cl TO4A FILECOLS $uslemlc Suloa InycStEatDE cerinn enotianal Dmh rM anxiety. In 1987 Carrigton creatcd cchmiquc unilatmy Iapning stimulatian Dcints clled Aculap Crai; introduced similar treatmentin Iqom whici became EFT HELEI - Iius: trcALIEIL were thcn \"enerlzed ~neri P cnnthent and Aeridian lirpin_ Tnerny Fcccnt &unict EFT has bcen prove Ahccuc ~alleviating SYILN(JILs suchashezduche MAMi [L depression [u], pncbia insomnuMS . and anxict Uaefaua Mha smtoms certain similanities with thosc FFT , cinccro cdece HB patients Furbrcaues tnatime andtrquency okthc therapics changed intinis; thc saneardiealinn needer perlomn exrecled elleci", " Br accesiin Past mcnoriciand EF Aesecnsincu Impact Datient Fnrouzh this proces cine-trd reduce emotion-L trauMA known HI Ltitzet alc-led Falients thcfni Eli smtoms Tusicnng WvcrMlha tananon Thcrcfore PMR Ftnieed Nccres Aecm inilmen manner different from EFT [tnutr4 {Pretrni EFL ", " Accordingly prcecnt clinical Invcstuatcs ciiccuvcncss tcatmicnt opton natients {nctien-ing aneer pnman aMpton touthinnkZ concare $ thc cnnventnnill mdnlatnn tcchninu of PMR: the4ey", " Mcthods", " 2Sufuhicctsunditid Paried Retieen Navember _01s and Fepnur Me Italot % narcinaen clinical trlzl The partic-pants were pulients di-gnused with HB verificd HF SCH) Juring screenin period Jotal partcipants Wcrc haecd the HB SCID chscd sublects s[Lq;_ FWMCUL Wcrc 1ssizncr tha EF [ tratment @TouN PMR treatment group Fanam' Allocation; 26 purticipants completed tke study and one *ubject in the EFT Eroup dropped out in the middle ofthe study IFleurc Mhe Dirt cligblc", " ALT Ths Amxlanal Frealom Ixhniau: IFFI Drozmn [urintu un llz EFT Lroup (EF Borrowing Benelit}", null, " nmmio DAmcnanie thc tWo groups dillered because HIcum AllacAliun %43 pEIIurIIEU ULL [Wu serarale UCLASJUIS", " Clnic antiovC\" Inetitutonal Rcnc Knard Hee University Husnital dong Korea (KHNMCOH Z0I} 01 02}. urg Garp", " Program Pratocol Fach suhject Emup cnvened hour cich Wccr undcruo EFI PR mJiME poviding' cJucalun On HB, the basies Concepts Tuedha andtime Ttactice FTT prognn nimet rcducc (nc smroms 0 HB Angethgt", " pnzmms perinrmed Le amerwar patticipania inetucted comt ft honework usine tle distnbuled wurkaneets aud s-f-Wiina Uhese errup Ctogrmt Kcr .TMTKAM Jehles and ^ ACTKA", " AM 4Iuup? WEIe Msrucled prclice the PIONIiLIII diily using; Ihe distrihutedtext and mp3 files AIl suhjects recorded thcnumhcrof aik: DNctkeand casfuleventetcaicdunth the tkerapy. The EFT UOLp 15) andPMRgowp(n = 121 boin nenormed thc prozram", " Graro Tcumed gouds Gathcred wcckly the me Und Incalion Tecerteetnun ~ther\"py and sell trining Lonks" ]

[ "1", "1", "1", "1", "2", "1", "1", "4", "1", "1", "1", "1", "1", "1" ]

[ "Is there any table on the top right of this page?", "Is there any table on the top right of this page?", "Is there any table on the top right of this page?", "Can you find any table on the top of this page?", "Is there any table on the right of this page?", "On the bottom of this page, is there a table?", "Is there any table on the top right of this page?", "Is there any table on the top right of this page?", "Is there any table on the top right of this page?", "Can you find any table on the top of this page?", "Is there any table on the right of this page?", "When you check this page, how many tables are in this page?", "Confirm if there are 1 figure in this page.", "Does this page include 1 table?", "Is there only 2 figure in this page?", "Does this page include 2 table?", "Can you find a table in this page?" ]

[ "True", "True", "True", "True", "True", "False", "True", "True", "True", "True", "True", "1", "True", "True", "False", "False", "True" ]

[ "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "counting", "existence", "existence", "existence", "existence", "existence" ]

[ null, " FIGuke Scherstk< of the cntirc EFT and PMR ptogramn protocol", " The program in the EFT group follo edthe EFT Borow - Lg; Benelit pratacol [15] follots;", " selting and confirming the Sequence: (imut *equence crquence EFT retraming_ EleM\"", " 2 3. Symiptont Assessment and Measurentent 'Iiols GSE (nc conaltion HB paticnts Hwabyung scalc; STAL; STAXL; ud SCL-Y- Mled FILCLL [4ey- Hwabyung nassc ASsee HA-relatcnsvmntomeano (nc scucflty of thc Boholoucal SladSIAA VcIc emnclajed atale denne antieinc neer in Ine patients Finally; the SCL-9-R was used Aseethaovcrall psrcholouical staiu; 0 thc partkcinants_ 4nluz", " Hwowvis Hwnb; unz Mcasut tc SCVCIIGY Hwabyung-related wumptoms HunpVuni' Palient; the first self reported sutrey Mex suring Hcab; unz and Ws constTucted Acon [161.", " Iicm s Hwabyung qubscalc Hwibyung charactetistics ind Hwzbyung svmptots have relalivelv ni nf internal consistensy, and the SyTP Hcabng dilicr cinincanty bcluccn Hwabiung goups inU UcpIe:Nan 4uups. Ie sile 15303525 3 IIpLOl of Hwrabyung during primary screening J0 points (16] dtce", " 2 3 2 STAL The STAI McAMM thc antich; raticnts Dcyclopcd Spielbeiger #il;} desicned Gbienuanm ~use *ereparted that MAal both the Anth trait SLlzno@ly stud; Vilsed [Ile Rorean Yersion Kha~ [17]: Ou", " G The STAXI js 4 tcwol for asasing the slatus &f anger STAXI was developedby Spielberger in 1937 aatoolto [csuIC CIOEEG O AECI in4 Cill uliized AIZ nomnaI nnarma netaoniit Gnarcensc anci dctinc M rngc feclings (uneing fturn [eelehdlly ttdjeint la displvtg GMMnecols anpcr; Ihe tralt ot anpcr cennro tcnacnc Intemmt wide range of conditions agcT PIOYOKIg Or Inuaung_ Figh: questinns ecn #ere includec [ncun ctntesion ragc, known Anzcr-out thc -uppresion subjccuye" ]

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[ "On the top of this page, is there a figure?", "Is there any figure on the bottom right of this page?", "On the top of this page, is there a figure?", "How many figures in this page?", "Is there only 1 figure in this page?", "Confirm if there are 1 table in this page.", "Does this page include a 'abstract'?", "Can you find a figure in this page?", "Are there any table this page?" ]

[ "True", "False", "True", "1", "True", "True", "False", "True", "False" ]

[ "existence", "existence", "existence", "counting", "existence", "existence", "existence", "existence", "existence" ]

[ " ALT Poxessu Mallio mlaraten Wp Mrformed PMR Lrou? (I51.", null, " called anger-in, and thc attcmnicd rcgulation culled arser-conttol (L8].", " Tic' Syroni CheclVisr %0-R (SCL-%-RJ; First devel - impfoycd DcroEcts scl-rcported mwt; chmensnnal clnic checli Lminnn DILSc$ ninc smptom scAlcs measuring Mnzaman (SOMA ubsessive-COIIpLLlve JUC lcneeruna[ snsiuvila (IS), cepressien Jttc n Khanaank (HOS) phahic ATNen (PHOE} Paranoid ideation; and Psychoticism (PSY ) YMILAICuIL (lutee DVCmA ACile JIC NLMIL plubil severity index (6S0}, Dositive symptom disiressindex (PSpI} the Positive symptom (PSTA Ol scI-IcpOf eiecue ~detailing; the subjective expetic#ces of patients Dbrrvcr cannol aetect Incrclone pfMAFS Siccning Pateng reqwrmg intcrcntcn Because this Tecuites Dalienis sel-iee Lneit nwn condmtion: cnablcs patients Orgnnize their Jnpton; AIAMS cedlnacel PAlLEl CcmICLALYC quicky [19] nEFL", " 2 Stotistical dalsls Suuc Inlzcd uSInE SPSS WVCISII Micrusult Eicel zuju nosttrenmment comnarisona inin fme avcragc Faluc coneaponeence analysls aU indeneneen inakciw7 ued ortnepre andpnamaimen: comnarisons bcteeen thc Erouns Daa Itom cacn Sak Wcn fru", " eviluiled determne Weetlict Were HOlpifiuIle[cIc Wsine Shipiro Wilk Wpen the dl WvCtL nantar mchn (STAI anxiety STAXI angct UCuSCL-YU-K AVX PHOB; HOS; PST, and P'SDI sales}, tns Mann- hitncy nonpntametric icst pcttornad dctermic Senincance cumpalcd haccina Fac 4oup_ When terickic waritinn W; nnninmetric lall STAL of STAXT SOMIn SCL-Ju E PHOR VEK AN PSY, GSI, and PST) the Wikoxan natchedpJuts signed ranks nerarmec 4306 signilicance chan\"e; -scurc the SCL-%O-R; nonparamcinc Icit thc Wilcoxon malched piirs siguedtanks aSeHoned [0I tha SOM; IS; DER; ANX , HOS PHOB, PSY, GSI and PST scalca", " Fnitemeni cnmninsn: Jnthin groups changes Occurred betwen the wceks | and Mtermi natlon of clnical cducation , 4nd Wcck [au tcrmmation attoing UDsereinil Ked using Ihedandar 0 verifcatin ctedirencs Sutistical ~significance Rea WAe desieniled AIL M[CHMUM-[U-[IC[ AILNsL in4 ner praxacol analysis terictme Etnuns alaletca analses formc hlinaed Fontrelled specialist", " Results and Discussion", " Riat", " Diflerrce Lahi Fck Teeue siunif cint eilerencet the FFT and PMR grp comnined (nclr [csncctivc bisclincs exccpt j0r thc PHUK xal which showed sotne diffetence Howevet, because the wrerall PHOB Scora than 70, which Ravcmnaini score; it canbeconcludedthatthcre was no signiicant clinical diretence Tee NEEDCAII ditference the mean age between the EFT (53,73 and PMR zroups (5Y.UU *87*cars 0.13}. Gol JEAIAA", " 32 Sigmyicart DitecucS Mle\" Hwobyuns Scale. Thcr sienicnt decreasL Lie Hwbvune fptum &Cille UWiiteen urlinc and %erk ,in thc EF [ @Toun concuomg tnc pfogJ h CFM highly signiticant clecreni the Hoahrny gmptom 'cale hetween hiscine and Wcck M", " PMR \"oup, stenificant deleai the Hwahyung symptom *cale between baseline aTdl wek 004J Kctwccn basciine and Vcck incre W1s J/s0 eunifcr deea IL HwilUIL $ IETIIL icl PMR group 04I Figure ", " Incrc Senicant dificrenccs bctwccn thc Kroun: diderences \"uaekerandalet", " 33.Swuticant Diticaeme: STAI In tlie EFT gowp Venineant decrenar both thc anxictu state and traIt hctueen hasclin anuud cl cuncluding tc Mugan] significant decteaxe Thantiet stille helween basclinc and %erk 9(D 0,U+6 Figure" ]

[ "1", "4", "1", "1", "1", "1", "1", "2", "2", "1", "1", "1", "1", "1" ]

[ "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "On the left of this page, is there a table?", "Is there any table on the top of this page?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "When you check the top left of this page, can you find any table?", "On the left of this page, is there a table?", "Is there any table on the top of this page?", "How many tables in this page?", "When you check this page, how many figures are in this page?", "Does this page include 1 table?", "Does this page include 1 figure?", "Does this page include 2 figure?", "Can you find 2 table in the page?", "Is there any table?" ]

[ "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "1", "0", "True", "True", "False", "False", "True" ]

[ "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "counting", "counting", "existence", "existence", "existence", "existence", "existence" ]

[ null, " FITTTAA The Hwabyung symnpototn Cumx n MiArd FTjup; (EF: Grou?); 0u (PMK Zioup; suptotu: bacllue 6m 5;Sth week sur\"e; snRom 9 %ih BunC ANuitt; Ee", null, " FIGURE ne SAI Axict sak comp'Ated and PMR Irnups aver time 0.05 {TFT TTuE . 005 (PMR group): STAIs- baselix sutvry; STAIs5: 5th neek survcyi SE: Yh week turyeY- [ne >N] nxetystate Sk #LAnLYed Wilcoxon sgud tanks Lmtel uing the", " Inthe PMR group there was significant decrease the #HIeLy slale U_SS| il [ali UUSzi Dclween bascline and%erk , Anter complctingtne prozram (nerc WAS significant change betwcen baseline and wcek %", " significant FTe post chaTge Lillerences STAl were tound bctwcen thc two @Toun;", null, " FTTAA 4 Tx STAXL angct ~comanedhrttkFFT PMk Eroun: 0le- Ie_ 0.05 (EFT Froup); STAXIs pieline A ncc: Qtvct: MAXNE YurYEY Aeuntty", null, " FIGURT Thc STAXIanger tralt scale compared hetwsen the FFT and FMK gtoups oct tinte (EFT group); $ 8075 (PMK gaup ; 98 UR Crou?); >A baseline Kit (ci STAX/t5; 5u Wrtk suttcs STAXt9 Jth Wtrk sut", " Spnifcail Diferevces STAX FFL goup; significant eMe\" thc angcr starc hctucen Viscc Week UuZI comnpletIE nOENM, thcn WAS siEnincant dccmA both tha anecr 0606)and tNia Muua andsi Figutes", " the PMR EMur; thete Wa; decrea Iheinver Iri: bctwcen bascina and Wccr whilc no senincant diticnnce" ]

[ "5", "1", "5", "1", "1", "1", "5", "1", "5", "1", "1", "1" ]

[ "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "Is there any figure on the top of this page?", "When you check the top left of this page, can you find any figure?", "When you check the top left of this page, can you find any figure?", "When you check the top left of this page, can you find any figure?", "Is there any figure on the left of this page?", "Is it correct that there is no figure on the right?", "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "On the top right of this page, is there a figure?", "Is there any figure on the top of this page?", "When you check the top left of this page, can you find any figure?", "When you check the top left of this page, can you find any figure?", "When you check the top left of this page, can you find any figure?", "Is there any figure on the left of this page?", "Is it correct that there is no figure on the right?", "How many figures can be found in this page?", "What is the number of tales in this page?", "What is the number of tales in this page?", "Does this page include a 'methods'?", "Are there any figure this page?" ]

[ "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "True", "4", "0", "0", "False", "True" ]

[ "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "existence", "counting", "counting", "counting", "existence", "existence" ]

[ " \"ils laund betWeen baselie ind Wcek [LL cunclusln [nanronnn", " ~significant diderncc agcI trait in STAXI wete found ketween the two gEoLps However; tnere stenincant diterence the tWo groups betwcen baseline and weck 5 (p um6and hseline and \"eek 0.0471. chacee Uncinesn", " 315 Sulficant Difjerewces SCLYiR the EFT goup,", " 315 Sulficant Difjerewces SCLYiR the EFT goup, Lnere signilicant the Paranoid iceatinn bctwcen bxscline Wccs UUIZ Ahcr concluston uf the progriu_the EFT %tou? shuwed significant deceises Nomitixalicn 0osi interneteonil sensilivilv 0,00}h, anxicly (p W hostility (p 0 003), paranoid Me MM) EpIESNI1- Uui6LDedoticiar 0,047}, the ohal ~verity index 001O), and he poiitVc wmptom UUM Y_u bctucch MNmAnuCek change", " the PMR group; there dccncae tha hostility scalc (p MMLI octccn bliclnc and Wcch Aftct tc Cunclainn nronlrn Ine PMk Zroup Jhcved anly dcfreasin @ tneency Ine hoetilit; <a Feern hasein iLd Wec", " 316 T-Score Assess'lev1t 0f SCL-S-R the EFT group SCL-Ju-R T-scote onl; showed sienilicant decneas parnnid ~oaehaun AelncATE MMn) Houcucrhctuct bascincandwcck o thercU a 'significant decrease SLALLZALOL DUXFI} . Intetpersun L sensitiv- Aa cepressinn (p Mnolantel; MM4 hostilic MI1naranol u paycholcGm U.UJX , [ne Aubill sveril ' Index DDI4, and the nositvc &Fmptomtota D UuiU Figure", " the PMR group; the SCL-JJu-R T-score only showed defreasin tencency Unehostilit scile Keem hiscine and%erk , UUus|and betwcen baslinc and %erk 9 0.074). Tle other SCales showed BCCALL 4cICILCC", " sipnifcant pre Dost chang\" dillerences wete nhsetved Ln Lhc 6CCi betwcen thc qouNs_", " Discuucsia Hwabyung: ahhreviated form Ulha wabyun_ Mrcholouical sndronc whcm cmotlon sucn 1 ilKCI Expleces ilct DEI' Jcc umul_led #Oul #ppEUmm[L Fenutum Phrical xmam: fhiticlerized cne piCXuIC hut T5h Jld & [ccln constriction thc nCca #deinhuld PIocess. Feelings IASmMCdI Jnser Aaal and haro terling cnancTu\" th< psychological smptoms ncicm medicallv Inicmemcicd 45 somallzatlon smctoms Cud pmlonued exthln' Emat Recu cnarcTheu otional angCr; it is often referTed iLLCI > HUIUMC ROICAM culiuic ecal ML Cucepiul \"hian is cccasionally linked #anget asinexplnation nfhis Weeas", " Studies HwabyUrS penaned etallale pacha opical amntoms antlch Ecl and cneiso According rcpurts HB patients ditlicult _ contralling anget cusedby extreme anget *P pIeesion; with svcrc anxIctV depnasi mood Tncsc", " palients\" Psychological nublems GUtE mnulliple > #plons inclucinz insnmni and keant alcitatinns. Marinus medn techniques hav hccn Fcnorted chcctve controlling [Mles SIIN(JILS HUIICTOUS €ses [ZD]", " Scucral mcent clinical tnals nave invcatipaico thc chccts of FFT SYIPIOm Anthety dlmuci including Phoblie tenxinnalheadxhe;d-pressicn , anxiety; and insamniz [R13], and 1 Iericw mroncd thatinc techniouc etcctlvc A@ainSt Gunalan Tii PTSD [21]. Coisideting [nerapewic {uccesses HTienectec mnae cleclive M controng pacholoecal problcn; rathci tan Thc phvsical SYIP[0l1L 3", " ancohtnanoswe-knox Featman therapies, PMR Ls Widcl Mico alcuatc Pall In cardlac ad othcr dixacs_ This behavioral treatmen: jims lo relax muscles by repesledly APPI;InE and relaxation; which reduces the physical Smrton; rarticipant: TCacyc Kancomizcd caniruller trizk: hve peen conducted iasesnz the elleci PMR adenomyasis patients (22] andbreast cancer patients The triak rcpurleu signficant MILAU: MJCILL quale; lileandaluiar Fnvscl Jn Nschuioc SMconi", " thts stud , Ihe PMR HoLp ULled scw Ercater decrense Mvsical Smntoms compared the EFT gTcup Hoxcc EFT group improyed more physical Sntonl the overall pacha nicl {inke anxicty and Anpcr cOmnarc? Toun pancuani thle HwabyLng; smptomn sle, EFT eaconfrmned i hinf etlective Hwahyung treatment in clinical conditinns; (nc EF ] \"oup soucd mcan scon 0l Icas than wecks uf folluw-up whih cunsicered HHiIEill Hwibul 4241\" VVR", " paricIpants In thc EFT 4oup Wcc mofc cifccuvc at con- Hwabyung syrnptoms, espexially anser ATO HLLED comtaren the PMR group. This CAni crnainci (nc SIAI SAX ano conatization ancT scalca RuM hen lare,th pnzram arzested method controlling Anthm aneCT evmntoma palients suffeting ftont HB utmer diseases \"lc SXEDCAEI decreni the antet stilte S pucnreandaner eamicncn both groups indicates that EFTis clearly ellective Cunttulis CuIIEII s(ale ul iLLCL Lulling couly", " 6ns stud; antiapaied that patients group uould GntFcn pfoup ncmcecncil dunnz (reiiment utilize tki; eect Lhe anil;s studi Las Grsizncd Maxmg; thi: cnenziatic cect MET Hlalca Al LCSICIL PMR Soup Was aLo suhiectec group therary the first 04The studi paticnts [cqulcd panticipatc pouR REAcut MMue @unmn' self-tkerapy Auuum Eroup sessions duringweeks 5 When (herarticirants Wen aakzcd throueh Tcck _ the EFT group showed significant Kmnbnanennenl eam CC tle PMR Htour ndcitian Comnatieon ncnucen Inahascline anc asscsemcnts show cd EF [ oup cxpcficnccd ucaicr McTI smplon; KFou Wkil patenis the PMR gToup ncnonanen YMILACUIL Curiul aet uiuuD Rei1S VAlJCII rtnun shonvec cnntnuag decna snptom Gen Uicelint Turing ADa" ]

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[ null, " FIGURE Thc SCL-%U-K ocsks <ompurd bxtwecn EFTA4 PMK 4oup: 0lt (Imtt\" MOS L; < 0o5 MFNK pmqupi 0.[ {PMR grup= SOM: somatizalinn baselra surrey: SOMS somatizalin Sth week SuTYey; SOM\": samatizatina \"h ncek surse} ; HOS hostiliry baseline HOcs uln calc; Host hasellin ANX arithaddincvakc- 45: anxiety Sth WTxsald; 4N1Y MuELy Yth Aacac", " 4' sell-[TiHI' Rg TeEUGO cratly demonstrates that the EFT caused much imrmted scl-tfaiinz crcc comrarco PAR clcct pouR similir petiseen hatn Amuts PTled Wctint", " addition the elfect = erour prCETAMI the EFT urouP continucd prc all duringscl-trainngaltcr thc hithe 4 nbner wnra Mnean; mnrr Wtaelc bring Krioimct naticnia oum than PMR technique Abo Inleried tHzl FI MIULEII ILcl JHCIL eltecne cO dlennzinatict thal haenttk distrihuiedind harcu Mdentical Tormal hecausc Ihcra sunifcinl changes SCVeIi sCilles compre Wcca DMoEram apected Fcqun Triod Ionper Uccc Ah full effect could", " 3} Linitations scnre was lessthan 70in the $C. 50 Ktce; Which mcans that tha Marticicants Actuau; could", " cene ronti cuolidnaldale Funer Judiz should conducted in patients with severe psychological problems. In addition numbci participanta Lnucs Eko significance of the finding< Ikis limitatinn shculd alleviated in further studies wnith big subjects Them jsakso unccrtalntvand Iack ol control programs conducted in hae aiter [neerrt*alnn #ver Nai", " Conclusions", " M ie 1-Wees PEOHIAIE shctss IHOI eiect Improv Sales nxycholozica svmptoms including aXIcTY ano anecr HB patients than PMR Program: The significan umnnrovemeni; ph tical <mploms Also jound in EF [ erour (2) TheFFT grop shcwed greater decreases in HB S3TP toms conpnred Fhee EToun Inc EF [ @Toun" ]

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[ "Is there any figure on the top left of this page?", "What is the number of figures in this page?", "Is there only 1 table in this page?", "Is there a figure in this page?" ]

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[ " is suwed PIOVEIIen ur sustained IIMIUYCIILEII cunnz self training cericke Wcer ucmonsacc cffccu= ccl-control LI EilIlenL PMK was prten etective Nwah; unz qutams canaieent wuth Iesuis Iton venttunl studies &FIng MMC FMK ~lect L ilevii inechical xmntan;.", " Conflict of Interests", " The authors declare that they have ompctng intcrests.", " Authors' Contribution", " Jin Wua Suh ard uIS' Hwin Lee s[ the EFT and PMR TuLM FTotoco this clinical trial r 4od Suh Sang omP RMAn Jong Woo Am Wm paper tnisttinl anaSum calculted the ampletize, lin An Enf Woo Kim performed tha EFT and PMR mcthodson HB patients theprogram, Sang conducled sury Jang WVova Kim initiated anl directed this studi one Chung editedtha hratpaper All authors Tcad iLD _pprUTE4 THC M FApcI Chunt Young", " Acknowledgment", " Tnisdudy supporledby the Minishry of Heahh Wate tuzh thc Roca Hcalth Industr'- Dc\"clerncnt Inaututc (KHID: HMIC1UA3u1((1G1", " Kcterencee", " AnixzIcal Paychaulc Aeucmalkut Dluxrustic Sui Ht Manlal p(Melal Disonlers American Pathixnc Arociatinn A*mt ~% suh; Slg, \"Syrpeons ducnotic crieenz Sndrome Ps\"chWte t\" Jurarsti'Htiurs , 7-122MJ NJmukni X L< epic-iniolozical Tud afhanhune- Fweanclall Okor Nctn,chicic, m Muul Seuym Remiein A nantc Frozressnt Rcr Waton; Mnc Ha Prunessio\"1s Kotuich Champlirn USA, [97}. CanGon Hol pficac Anbravlated pitgltay MuSIc tlaxation Ittg; OAEEAMtMct Dehaxnti_ malmicin mearp Cam Consuting Inl Clirica Pchulu ~ns_S7IJ Vuncamplorl; Correll TWSchtrur eal Fouressiv Dersans with achlzaphren aslemaic MNt IAAcunerlled Cliniclechohilitdion FT4S Shcu; Irvln: Etlcct & Vio Wielte Mux rehxtlon olocd prexul a0d pn chosocial satus I cllents withesaentlalhvpertenalon In Tiiwan ` Huliatic Aumeuci KmPP_ wanr (Cput Wte altyoliopnic aictal ~Eaunr 4\" nnn Fux", " sckerassALSI Erient ~hobas Hwnbuntand n LEpIe te dicucdc\" Wuctallu Ori HTalercansvchurttalI6 Kouz Suundide45, Alcxcjouhna \"hottalecs RChrous{,JnC. Darviri Edectoltheemotionaltreedam Uxhnlau_ NctauGu QAum' Cnte ENNET lensian tRpeidiche uuiern:1 NnLOxuIE contrelledtnal; Hdlun\" Ie Wuur'ul? Maelc e Acku Healltug,tl Ckc Hawk Xrauka Fsuhological tJur SnRomn (prorieni S UenuEualnram (xhniqus; cindnmniCanemltria Ilanclllea Meutut Dixux PP: 15}-J6o, Z0L3 ChurchM; De Asls, An4 4.[ Froxks Brlc uroun Iner_ venli USt_ eruliona Intedom kechniqu: UepressIJ colleee stucenta Fnanmnn cantrcetral Ikoressh Kecuma Ttert Ailici 257172 Duley WIl Folpae Uattt Caringlon; Lc HiRT Faronenlencneen-hleunicruentnn ennctconal Lieluom Irchniqurs (EFT} lor reducing specilic phobias amallanlmal: bwrnal % Clinical Fsychology , LiSun 4mM Hennt Ledyt Unbaeanne ~Pilol lud\" U tmoliunal Ireeuon Iechniuues wholislic nybrid Lfntcc TMM&t rement deecmaxAan Ae Mn Uhn IccIliqule , Alld (ugililve Ochavlutal theIepy AMeni anxler; nayersita Fudenl Eanlure\" Kue Iu\"r /ma unscIc\"ct Ars Ht Ju \" 34u,10u) Rcmscm#mu Karkan Wgimf Tnnmn Traiiug; Rescurch Press, Chumpaign_ IlCd Crig Ihe EF Kt Fachulogt Wan Gana Rosz Calil, USA UuII au tmeniar KldFATG Hwbyurs Scile; Caoe Cnicei Clirica Ksnhulust; 27 O 237-252 [17] FTKim and D aud-based onthsundardizat HI nens Rami [ Slue Hun Chun Aneec ploud paunc karean Adapualon Mthe aate- IraIt Anucr exnms M Mecntam nMr\"uemutarrauAic Dyheluyh [19] 1 H Kim_ d H Svmplom checklix-Q retsian \"SCL \" Rlin psichiatric autpatiert Hetut Hcaltt AJu Ice And Cnicaluldeline^ (urrutal prychathauJDY Altd IILAIJUtuIlx71t), Jurjttai lnu Mewons\"dzlutn; val_ ZUI} fentlln ~Kapi Inatnieni PED: \"b p\"chological EXPOSue #Ih acupoint tappin _ hchn Fsldlclt 47no 402, Zui\"_ Pothomf Schmr Wnskemar ~Randamn Cntale 4entaa Alnts ts Aa e Eum esaIaGe coxparc_ procrslve musch Weaann htela Caxt palkntt unectuolt Jaluvant tadiotctaps KKa sud;, FMCCINCE artice Iol 2 Zhan Z Ch Ellect ol pragexslie Tusculir Iclxation IILIDING on _nxlet%; cpireslol and quJity 4 Iik ul cutdutuctt Rusis Aticuit $ UIlclctt T4chu Pue Mtltuur Erint, Wana" ]

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[ "Is there any figure on the bottom left of this page?", "Confirm if there is 'introduction' in this page.", "Is there any figure?", "Is there any table?" ]

[ "False", "False", "False", "False" ]

[ "existence", "existence", "existence", "existence" ]

[ " Fon dolraphin rleasn z hamone Lenpy Elroxwm Obstetri Gynecekgy Uoneduat JMEAMMue 124] !H Rn; Park [, W Kim; Mn;Anh Nun Deielopmtnt Ld ulidalion U Ihe Hwa-Brunp scale. Tl Korcun Wmal Wfailall xchalog? , sol. %,00 ! FP. 257 - 4f Ml5 HnJcg}." ]

[ "3" ]

[ "Can you find any table on the top right of this page?", "Confirm if there are 3 table in this page.", "When you check this page, can you find 'methods'?" ]

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[ null ]

[ "5" ]

[ "When you check the bottom right of this page, can you find any table?", "What is the number of figures in this page?", "How many tables can be found in this page?", "Can you find 1 table in the page?", "Is there a figure in this page?" ]

[ "False", "1", "0", "True", "True" ]

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[ "Open Access\n", "Empirical and conceptual investigation of\nde-implementation of low-value care from\nprofessional and health care system\nperspectives: a study protocol\n", "1,2\"\ntenna Hasson0, Per Nilsen, Hanna Augustsson and Uirica von Thiele Schwarz'\n1,2\n", "Abstract\n", "Background: A considerable proportion of interventions provided to patients lacks evidence of their effectiveness.\nThis implies that patients may receive ineffective, unnecessary, or even harmful care. Thus, in addition to\nimplementing evidence-based practices, there is also a need to abandon interventions that are not based on best\nevidence, ie, low-value care. However, research on de-implementation is limited, and there is a lack of knowledge\nabout how effective de-implementation processes should be caried out. The aim of this project is to explore the\nphenomenon of the de-implementation of low-value health care practices from the perspective of professionals\nand the health care system.\n", "Methods: Theories of habits and developmentai learning in combination with theories of organizational alignment\nwill be used. The project's work will be conducted in five steps. Step 1 is a scoping review of the literature, and\nStep 2 has an explorative design involving interviews with health care stakeholders. Step 3 has a prospective design\nin which workplaces and professionals are shadowed during an ongoing de-implementation. In Step 4, a\nconceptual framework for de-implementation will be developed based on the previous steps. In Step 5, strategies\nfor de-implementation are identified using a co-design approach.\n", "Discussion: This project contributes new knowledge to implementation science consisting of empirical data, a\nconceptual framework, and strategy suggestions on de-implementation of low-value care. The professionals\nperspectives will be highlighted, incuding insights into how they make decisions, handle de-implementation in\ndaily practice, and what consequences it has on their work Furthermore, the health care system perspective will be\nconsidered and new knowledge on how de-implementation can be understood across health care system levels\nwill be obtained. The theories of habits and developmental learning can also offer insights into how context\ntriggers and reinforces certain behaviors and how factors at the individual and the organizational levels interact.\nThe project employs a solution-oriented perspective by developing a framework for de-implementation of low-value\npractices and suggesting practical strategies to improve de-implementation processes at all levels of the health care\nsystem. The framework and the strategies can thereafter be evaluated for their validity and impact in future studies.\n", "Keywords: Disinvestment, Unlearning, Habits, Ineffective, Abandon, De-adoption, Decrease use\n" ]

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[ "Background\n", "The importance of basing care practices on evidence\nand empirical research findings rather than on experi-\nence or beliefs is widely accepted in health care [1].\nHowever, putting evidence from research into practice\nhas been shown to be challenging, as indicated by the\nrenowned research-practice gap [2). This gap tends to\nbe approached from the perspective of research (ie., that:\nthere are efficient interventions that need to be imple-\nmented). However, another aspect of this gap is that:\nsome health care practices (eg, interventions, programs,\nand services) lack evidence of effectiveness and may\neven be harmful. Such low-value care practices, i.e,\npractices which lack current, best evidence, should\ntherefore be abandoned, which is often referred to as\nde-implementation [3).\n", "Use of low-value care practices is common. Estimates\nshow that 12-15% of patients receive at least one low-\nvalue practice a year [4), and 72% of physicians in a\nstudy conducted in the USA stated they prescribe\nunnecessary tests or procedures at least once a week [5).\nThe most common type of low-value care is likely an\ninappropriate use of an effective practice for patients for\nwhom the practice's benefit has not been demonstrated\n[6]. The yearly cost of low-value care was an estimated\n$8.5 billion for the USA Medicare population, which\nconstitutes almost 3% of the total Medicare annual\nspending on services [7]. Thus, the considerable preva-\nlence and unnecessary costs of the use of low-value care\nhave made this a major problem for health care systems.\n", "While implementation of evidence-based practices has\nreceived substantial attention, the challenges of de-\nimplementation of low-value care have so far attracted\nlimited interest from researchers, professionals, and\ndecision- and policy-makers [3, 8]. Lists of non-\nrecommended practices such as Choosing Wisely [6]\nhave become common, yet they have little chance of\nleading to improvements without sufficient knowledge\nabout efficient de-implementation, i.e, translating the\n\"what\" should be de-implemented into the \"how\" this\nactually should be carried out [6, 9-12).\n", "The challenges of de-implementation decisions and\nprocesses can be considered from both the perspectives\nof health care professionals and the health care system.\nFor health care professionals, de-implementation\ninvolves ceasing to do something. This might require\nunlearning and breaking ingrained habits, which tends\nto be difficult [13-15). It can be a threatening process to\nchallenge well-established, entrenched thoughts and\naction patterns [16), particularly for those invested in\nthat practice. Various practices can be deeply embedded\nin a person's position, status, values, and identity. Aban-\ndoning a practice can therefore be emotional, touching\nupon issues such as what is considered valuable\n", "knowledge, ethics, and professional roles and expecta-\ntions. Thus, de-implementation may act as a cognitive\nstressor by evoking contradictory demands. It may also\nact as an emotional stressor, causing ethical distress in\ninstances, for example, when professionals know that\npractice is not recommended any longer but their role\nor status is associated with that specific practice. Ques-\ntions concerning how health care professionals deal with\nde-implementation, what responses they have to de-\nimplementation, and what influences this process have\nnot yet been systematically investigated. Hence, there is\na need for research about de-implementation from\nhealth care professionals' perspectives.\n", "Stopping certain practices often requires decisions at\nmany levels, from the group, department, and\norganizational levels to regional and national levels.\nThus, de-implementation of low-value practices is an\nissue at all levels of the health care system [17-19).\nPrevailing norms, values, work processes, and financial\nand professional interests play crucial roles in de-\nimplementation decisions and processes [12, 20]. This\nimplies that the decisions of individual professionals\noften depend on the culture of their professional groups\nand/or the decisions made at other levels of the system.\nThus, research on de-implementation requires a system-\nlevel perspective. However, research on how de-\nimplementation decisions and processes are managed in\nhealth care is limited.\n", "Factors that influence implementation are well-known,\nhaving been identified in many empirical studies and\nsynthesized in numerous so-called determinant frame-\nworks [21], eg., Consolidated Framework for Implemen-\ntation Research [22), Promoting Action on Research\nImplementation in Health Services [23], and Theoretical\nDomains Framework [24). These frameworks categorize\na number of interdependent determinant domains\nencompassing different levels, from the individual pro-\nfessional, team, and department to the organizational\nand societal levels. However, the extent to which the\nsame or similar factors or domains also influence deci-\nsions and processes concerning de-implementation of\nlow-value practices has not been investigated.\n", "There is some empirical research that points to the\nimportance of individual factors for de-implementation\ndecisions and processes. For instance, it has been shown\nthat physicians' use of low-value care is strongly influ-\nenced by patient preferences and wishes. Over half of\nUS physicians reported that they would order tests if\nthey were requested by a patient even if they knew these\ntests were unnecessary [5]. Fear of malpractice or missing\nan important diagnosis was the main reason, implying that\nthe tests, although low-value in specific patient cases, of-\nfered a sense of security for the physicians. Further-\nmore, physicians' perceptions of the importance of\n" ]

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[ "On the bottom right of this page, is there a figure?", "Does the author discuss the 'Background' on the top of this page?", "Is there any 'Background' on the top left of this page?", "Is there any 'Background' on the top left of this page?", "Is there any 'Background' on the top left of this page?", "Can you find any 'Background' on the left of this page?", "How many tables can you find below 'Background'?", "When you check the page, are there any figure below the 'Background'?", "When you check this page, how many table can you find on the top of 'Background'?", "Is there only 2 table in this page?", "Can you find a 'background' in this page?", "Is there a table in this page?" ]

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[ "de-implementation are influenced by how convincing\nthe lack of evidence for the low-value practice is and\nwhether there are alternative practices available [25].\nPhysicians have also shown uncertainty in their know-\nledge to interpret research findings, which causes dif-\nficulties in their ability to make decisions about\nabandoning low-value care (26].\n", "Concerning the organizational and other system\nlevels, empirical research thus far suggests that de-\nimplementation decisions and processes are affected by\nfactors such as political interests, invested interests,\nand community expectations together with media\nengagement [8]. There is also a risk that cost consider-\nations are prioritized over effectiveness [25]. Furthermore,\nsteering mechanisms, including financial incentives, may\ninfluence the practices being used. For instance, fee-for-\nservice payment models may incentivize the use of\nlow-value care practices [27]. Furthermore, a lack of\ndecision-support systems, poor quality of data, and poor\ncommunication and leadership potentially influence de-\nimplementation of low-value practices (8, 26. 28).\nShepperd et al. [26] found that administrative health care\nmanagers in the UK in general lacked understanding and\nknowledge about how to efficiently de-implement low-\nvalue care. They also emphasized the importance of social\nprocesses with sense-making and goal clarification to\nsucceed with de-implementation processes. In practice,\ndecisions to stop use of low-value care were often pro-\ncesses that lacked clear structures, with opportunities to\nmonitoring the success being few [26]. In sum, existing\nempirical research suggests that the individual level and\nmany system levels are intertwined in de-implementation\ndecisions and processes.\n", "The aim of this project is to investigate de-implementation\ndecisions and processes concerning low-value health care\npractices from the perspective of professionals and health\ncare systems.\n", "Specific research questions:\n", "1. How is de-implementation described in the literature\nconcerning (a) determinants influencing de\nimplementation decisions and processes. (b) interven-\ntions that have been used for de-implementation, and\n(c) existing frameworks/models for de\nimplementation?\n2. How do health care actors (e.g. professionals.\nmanagers and administrative management) reason\nabout the de-implementation of low-value care\npractices, and how can variation in de-\nimplementation practices be understood?\n3. How do health care professionals approach de-\nimplementation processes in practice, and what are\nthe cognitive, emotional, and behavioral responses\nto these de-implementation processes?\n", "4. How can factors that influence de-implementation\ndecisions and processes be categorized and synthesized\ninto a conceptual framework?\n5. How can de-implementation be facilitated at different\nhealth care system levels (national, regional,\norganizational, and individual)?\n", "This project will apply theories of relevance for under-\nstanding and explaining de-implementation at different\nsystem levels, from the individual to the societal. Theor-\nies concerning habits and developmental learning in\ncombination with theories of organizational alignment\nwill be used. Health care professionals perform hundreds\nof tasks each workday. Many of these are executed\nhabitually, that is, without deliberation or conscious\nawareness [29). Habits are highly necessary for the indi-\nviduals and the system but become problematic when\nthe habitual behaviors need to be modified, as in the\ncase of no longer using low-value practices [30].\n", "According to developmental learming theory, the first\nstep in ceasing habitual behavior is making its practi-\ntioners conscious of it [31]. This can be done, for\ninstance, through education or information. Yet, mere\nknowledge is rarely sufficient for changing behaviors\n[32]. From theories on developmental learning and\nhabits, this can be understood in at least two ways: (1) It\nrequires more time, effort, and motivation to change\nhabitual behavior than to continue doing what normally\nis done and (2) the habitual behaviors are embedded in a\ncontext, which has many cues that elicit the behaviors in\nquestion, whereas there are few or no cues for an alter-\nnative, new behavior (30, 31]. The latter links the theories\nof individuals' habits to organizational theories, indicating\nwhy habits are context-dependent [33, 34].\n", "The theory of alignment describes how organizational\nbehaviors and practices need to be aligned with the over-\nall goals, systems, and functions that are in place [34).\nThis implies that individuals' opportunities, motivations,\nand abilities for abandoning their work practice habits\nare dependent on the expectations, norms, and values in\nthe organizational context. The organizational context, i.\ne, what is appreciated, possible, encouraged, supported,\napplauded, and rewarded at a workplace, can often be\nexpected to have greater impact on individuals' behaviors\nthan more abstract factors such as scientific knowledge,\nclinical guidelines, or other recommendations of care\npractices (32).\n", "The process of habits goes the other way around, as\nwell: The habits of the individual become the routines of\nthe collective, emphasizing the interaction between the\nindividual and the context in which he or she works.\nThe routines become norms, representing the unwritten\nrules for a profession (e.g., physicians, nurses) or other\nsocial groups (e.g., work units) when these are socially\n" ]

[ "1", "1", "1", "1", "3", "3", "1", "1", "1", "1" ]

[ "Is it correct that there is no table on the bottom left?", "Is there any figure on the top right of this page?", "Can you find 2 table in the page?" ]

[ "False", "False", "False" ]

[ "existence", "existence", "existence" ]

[ "approved and shared. Norms in turn provide a sense of\ncommon direction [34-36]. The powerful impact the\nnearest organizational culture has on health care profes-\nsionals behaviors when it comes to implementation of\nnew knowledge has been confirmed in numerous studies\nfrom implementation science [22, 37, 38]. Thus, the\nsurrounding social system provides strong cues for\nbehaviors.\n", "Methods\n", "This project has multiple research designs and consists\nof five main steps, which correspond to the five research\nquestions. Step 1 is a scoping review of the literature.\nStep 2 has an explorative design involving interviews\nwith health care stakeholders. Step 3 has a prospective\ndesign in which workplaces and professionals are\nshadowed during an ongoing de-implementation. In Step\n4, a conceptual framework for de-implementation will\nbe developed based on the previous steps. In the 5th\nstep, strategies for de-implementation are identified\nusing a co-created design approach.\n", "The study will be conducted in Stockholm County\nCouncil in Sweden. Sweden has 20 county councils/re-\ngions that are responsible for provision of health care in\ntheir regions. Stockholm County Council is the largest\none in the country. It provides all types of care and health\ncare locations, including acute care hospitals, psychiatric\ncare, primary health care centers, and rehabilitation.\nStockholm County Council health care organization has\napproximately a total of 36,000 employees. Health care in\nSweden is largely publicly funded. All residents are\ninsured by the state and have equal access to health care.\nOut-of-pocket fees are low and regulated by law,\n", "Step 1-scoping the literature on de-implementation\n", "This step involves a scoping literature review to under-\nstand how de-implementation is described in the scien-\ntific literature. The scoping review will follow the steps\noutlined by Arksey and O'Malley [39). Three research\nquestions will be addressed: (a) which determinants for\nde-implementation decisions and processes in healthcare\nhave been described, (b) which interventions have been\nused for de-implementation in healthcare, and (c) which\nframeworks/models for de-implementation have been\ndescribed? Relevant studies will be identified through\nsearches in electronic databases (i.e., Embase, MED-\nLINE, and Web of Science) and through searches of\nreference lists and of key journals, such as the Imple-\nmentation Science. Two researchers will review abstracts\nand full articles to determine inclusion or exclusion.\nStudies in English that address one or more of the re-\nsearch questions will be included in the review. Studies\nfocusing solely on prevalence of overuse will not be in-\ncluded. The inclusion criteria for studies included will\n", "be developed during the course of the process (rather\nthan strictly pre-defined) [39]. In the next step, key in-\nformation will be extracted from the articles and entered\ninto a data extraction form. Extracted information will\nbe both general, for example, study setting and popula-\ntion, and specific, addressing the research questions, e.g.\ndeterminants found to influence de-implementation or\ninterventions used to facilitate de-implementation.\nFinally, the data will be summarized, collated, and re-\nported. An overview of the extent, nature, and distribu-\ntion of the studies in the review will be presented. The\ninformation from the studies will be organized thematic-\nally and summarized in order to respond to the research\nquestions. The themes will be inductively developed\nbased on the empirical data and determined during the\nanalytical process.\n", "Step 2-describing health care actors' reasoning\nconcerning de-implementation\n", "This step involves a qualitative data collection which will\nbe carried out in accordance with the COREQ checklist\n[40]. Semi-structured interviews will be conducted to\nunderstand how health care actors (e.g.. professionals,\nmanagers, and administrative management) reason\nthrough de-implementation and how variation in de-\nimplementation practices can be understood. We will\nstart with identifying two to three low-value care prac-\ntices (i.e, methods that should be de-implemented)\nthrough key stakeholders at the Stockholm County\nCouncil. This includes the local Health Technology\nAssessment organization, senior managers, frontline\nprofessionals, and individuals with a formal responsibil-\nity for medical, nursing, or other areas of care (eg, chief\nmedical officers). When a specific low-value care prac-\ntice has been identified, the managers of all work places\nin the Stockholm County Council where this practice is\nor has been used will be approached. The managers are\nasked to forward an invitation to the interviews for indi-\nviduals who have knowledge and experience relating to\nthe specific practice. Those individuals responding to\nthe invitation will be approached by the research team\nwith a clarification of the interview aim and practical de-\ntails. Thereafter, we will also use snowballing to recruit\nadditional stakeholders in the same and other respondent\ngroups (different professionals, managers, administrative\nmanagement). Additionally, during the interviews, we will\nask interviewees to identify additional low-value care prac-\ntices that have been or should be de-implemented. The\nparticipants will vary in terms of professions, their posi-\ntions in the health care system, the low-value care prac-\ntices they have experience with, and the health care\nsettings. This variation is sought to achieve a richer\nvariation of de-implementation. We hypothesize that\ndecisions and processes differ between the low-value care\n" ]

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[ "practices. Thus, the participant selection is purposive sam-\npling and the recruitment will continue until multi-level\nsaturation is achieved: that is, we strive for sufficient infor-\nmation across professional groups, work units, and de-\nimplementation cases. We estimate that this will require\naround 30-50 interviews.\n", "An interview guide will be developed based on the\nguiding theories and the literature review. As de-\nimplementation might be perceived as a delicate subject,\nbuilding confidence between the researchers and the\nrespondents will be of importance to ensure that the\ninterviews reflect reality. We attempt to establish this by\nusing researchers with extensive experience in interview-\ning as well as in evidence-based practice in health care.\nTwo members of the research team will be responsible\nfor the data collection and analysis. The remaining\nresearch group will act as informed outsiders. They will\nparticipate in iterative debriefing sessions to support the\nanalysis and interpretation of the findings. Thus, data\ncollection, transcription of recordings, and analysis will\nbe done iteratively. A hypo-deductive approach following\nthe step outline by Fereday et al. [41] will be used to\nanalyze the data. We will start with the hypothesis from\nthe theories of habits, developmental learning, and align-\nment and test these in several steps with the data. The\ninterviews will be audiotaped and transcribed verbatim.\nThe nVivo software will be used for the data analysis.\n", "Step 3-following professionals' approaches to\nde-implementation\n", "This step is a prospective, longitudinal case study focus-\ning on how health care professionals approach a de-\nimplementation. A case will be identified primarily from\nthe Swedish National Board of Health and welfare's\n\"not to do-list\" [42] and other guiding documents (e.g.\nclinical practice guidelines and regional care programs)\nin collaboration with health care stakeholders. There will\nbe three national clinical guidelines including \"not to-\ndo-lists\" from the Swedish National Board of Health and\nWelfare during 2018. The final selection of a case from\none of these guidelines will reflect a low-value practice\nthat is common and will involve several professional\ngroups and in which there has been a clear formal deci-\nsion to de-implement that practice.\n", "After deciding which low-value practice that will be\nstudied, work units within the Stockholm County Council\nwhere this practice is used will be approached. An invita-\ntion to participate will be sent to the managers of those\nunits. The de-implementation process will be followed over\na period of 12 months in all, or a selection of, work units.\nWe estimate that two to four work units will be needed to\nreceive sufficient variation in a de-implementation process.\nThe balance between the number of work units and the\nnumber of individuals within work units will be determined\n", "based on information about variation derived from steps 1\nand 2: If most of the variation in de-implementation deter-\nminants exists at the individual level, we will recruit more\nindividuals and fewer work places, and vice versa. The data\nwill be iteratively collected and analyzed, which will allow\nus to observe potential data saturation across individuals\nand units. We will start with two work units and at least\neight individuals at each work place, reiteratively collecting\nand analyzing data and expanding the data collection until\nmulti-level saturation is reached. Health care professionals\nfrom all professional groups involved in the use of the\nspecific work practice will be the main informants.\n", "Multiple data sources will be used to capture the de-\nimplementation process. Structured observations will be\ncomplemented with interviews and collection of\ndocuments concerning an ongoing de-implementation\nprocess [43]. Observations will be focused on staff meet-\nings and other work situations where de-implementation\nmay be discussed, and paper trails such as minutes of\nmeetings and other documentation will be gathered. No\ndata where patients can be identified will be collected.\nThe observations will be conducted in accordance to a\nstructured process, using a pilot-tested protocol [44, 45).\nThe protocol will indicate time and the activity's pre-set\nagenda, content (e-g. what is verbalized by whom in\nspeech or writing), and the process (e.g., types of activ-\nities and procedures) and other potential categories of\ninterest based on the guiding theories and the literature\nreview. The observer makes field notes in the protocol\nduring or after each observation. The complementary\ninterviews will be based on the observations and enable\nthe researchers to ask follow-up questions based on pre-\nvious observations. An interview guide will be developed\nbut allow flexibility based on the observational findings.\nOne member of the research team will carry out all data\ncollection at this step and is responsible for the analysis.\nAs with the previous step, the remaining research group\nwill support the analysis and interpretation by acting as\ninformed outsiders in iterative debriefing sessions. The\nmultiple source data will be triangulated. The interviews\nwill be audiotaped and transcribed verbatim. The nVivo\nsoftware will be used for the data analysis.\n", "Step 4-developing a conceptual framework\n", "Addressing research question 4, this step entails develop-\nment of a conceptual framework to describe and categorize\nvarious influences on de-implementation, (determinant\ndomains), including individual- and system-level determi-\nnants. The framework will be based on the literature review\nand findings from the empirical data from the previous\nsteps. A comparison will also be made with one of the exist-\ning determinant frameworks for implementation. We have\nexplored numerous potential frameworks, many of which\ninclude the same or similar determinants [21]. We plan to\n" ]

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[ "use the Consolidated Framework for Implementation\nResearch (CFIR) [22-24). since it is one of the most\ncomprehensive frameworks. It is also sufficiently broad\nto allow for an explorative, inductive approach to col-\nlecting data. This approach is important since there are\nfew studies which have investigated and attempted to\ncategorize determinants of de-implementation. Further-\nmore, CFIR is the most widely used determinant frame-\nwork by implementation researchers, according to an\ninternational survey of 223 implementation researchers\n[46]. A preliminary version of the conceptual frame-\nwork for de-implementation will be reiteratively tested\nwith health care stakeholders as well as national and\ninternational collaborating researchers to obtain opti-\nmal scientific rigor and practical usefulness.\n", "Step 5-identifying strategies for de-implementation\n", "In this step, strategies will be developed and feasibility-\ntested to address how de-implementation can be facili-\ntated at various health care system levels to ensure that an\neffective process is achieved. The framework developed in\nstep 4 will be the foundation for the strategies and inter-\nnational and national experts on de-implementation,\nand stakeholders involved in the previous steps will be\ninvited to participate in workshops to develop the strat-\negies. A structured process, the co-created program\nlogic (COP), will be used to synthesize knowledge about\nstrategies for de-implementation from the previous\nsteps and across the different participants [47]. This\nmethod is used to utilize knowledge and experience\nfrom multiple sources and create a shared understand-\ning among the participants. COP is flexible in terms of\nnumber of participants; the final number will be de-\ncided based on the number of relevant participants that\ncan be identified. Following the COP process, the stake-\nholders will be asked to rate the feasibility and import-\nance of each strategy. Descriptive statistics will be used\nto analyze the data from the feasibility questionnaires.\n", "Discussion\n", "This project has the ambition to make substantial con-\ntributions to implementation research and practice with\nregard to de-implementation of low-value care, thus\naddressing the well-known gap between research and\npractice. First, it contributes via empirical data on how\nde-implementation of low-value practices is handled by\nprofessionals. This offers insights into how professionals\nmake decisions and reason through de-implementation\nin daily practice and the consequences this has on their\nwork. Importantly, de-implementation will be investi-\ngated from the perspective of several professional groups\n(rather than solely focusing on physicians as has been\ncommon in previous studies) and line managers (in\naddition to administrative management, which has been\n", "the focus of prior studies). Thus, the current project has\nthe potential to contribute to a deeper understanding of\nde-implementation of low-value practices in the health\ncare setting.\n", "Second, the health care system perspective on de-\nimplementation of low-value care will be highlighted.\nStopping certain work practices might require decisions\nand actions at multiple levels, from the team or unit to\nthe organizational, regional, and national levels. The\nproject will contribute to knowledge of how de-\nimplementation can be understood across health care\nsystem levels, which is important in facilitating effective\nprocesses across the whole system. The importance of\ncontextual perspectives in implementing new knowledge\nhas increasingly been emphasized in implementation\nresearch [22. 37, 48).\n", "A third contribution concerns the project's use of theor-\nies of habits, developmental learning, and organizational\nalignment. The relevance of these theories has been sug-\ngested [29] but few empirical studies that apply them have\nbeen conducted. Theories of habits and developmental\nlearning can offer insights into how context triggers and\nreinforces certain behaviors (but not others) and how fac-\ntors at the individual and the organizational levels interact.\nThe theories will be used to analyze how different factors\ninfluence health care professionals' continued use of low-\nvalue practices that should be abandoned due to their low\nvalue and to explore what cues and opportunities are\nneeded to stimulate abandonment of such practices. The\ntheoretical approach of the project facilitates insights into\nhow and why certain factors have impact rather than\nmerely producing lists of factors having impact. Fourth,\nthe project aims to develop a conceptual framework for\nde-implementation of low-value practices. This can be\nused as a tool in future studies that aim to systemat-\nically approach de-implementation. The framework\nwill illustrate all levels of the health care system in\nrelation to abandonment of low-value care practices.\nFifth, the project has the ambition to develop theory-\nbased strategies to improve de-implementation pro-\ncesses at all levels of the health care system. Because\nde-implementation is an under-researched area, there\nare few solutions available for researchers and practi-\ntioners. Therefore, this project contributes potential\nsolutions that the research community thereafter can\nevaluate for their impact in future studies.\n", "This project is explorative in character due to limited\nknowledge about the phenomenon of interest, ie., de-\nimplementation in health care. The project begins with a\nstudy (Step 1) aimed at achieving improved understanding\nof the concept of de-implementation and the terms used\nto denote this. The other steps explore the determinants\nof de-implementation, and the final step is aimed at iden-\ntifying potential strategies that can be used to improve the\n" ]

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[ "process. However, the project does not involve any inter-\nvention evaluations, which will be an important next step\nafter more knowledge has been generated.\n", "A scoping review methodology has been chosen since\nthe research field is still immature. This kind of review\nis valuable in exploring what kind of research has been\ndone in an area, and unlike in systematic reviews, the\nquestion is often wider, and studies with all types of de-\nsigns are included [39]. The literature review is expected\nto offer a broad understanding of the key studies and\nconcepts underpinning the field. An important strength\nof the project is the combination of different methodo-\nlogical approaches (literature review, empirical data,\nconceptual work, and strategy development). We will be\nable to gain insights into de-implementation by using\nboth empirical and conceptual perspectives. Further-\nmore, several levels of the health care system are ad-\ndressed, which is important for understanding the\ninterplay between individuals (e.g., habits), organizations\n(e-g., norms and climates), and health care systems (e.g.\nrules and regulations).\n", "Acknowledgements\n", "The authors would Ike to thank Associate Prafessar Kerstin Roback for\nvakuabile comments on the project opplicatian and the Stockholm County\nCounal for particpating in the project.\n", "Funding\n", "This study has received research grant tundng tom the Swedish Research\nCouncl for Heakh, Working life and Wefare (FORTE (project no. 2017-0449\nater a compertive peer-review process. Forte is one of the largest national\nresearh funders founding both basic and needs-driven research, distribuing\nround 550 milon SEK every year to both\n", "Availability of data and materials\n", "The datasets used wil be avalable from the corresponding author on\nreasonable request.\n", "Authors' contributions\n", "HH, LVTS, and PN deságned the project. HH secured funding for the project\nand was esponskle for the ethical application. HA drafted the fist version\nof the study protocal based on the orignal appiation All authors discussed\nthe draft, revised k and approved the final manuscript.\n", "Ethics approval and consent to participate\n", "The project has been reviewed by the Regional Ethical Review Board in\nStacktiolm ief na. 201 /2211-3151 ond found not to need any ethical\npporovid. Nevertheless, al portioports wil be treted in accordance with the\nethical guidelnes Informed consert will be obtaned from all study\nparticipants. In the case of sefusal, these indi vidualh wil not be nduded in\nthe data set used for anahses.\n", "Competing interests\n", "The authon deciare that they have na competing interests\n", "Publisher's Note\n", "Spinger Nature semains neutral with regard to jurisdictional caims in\npublished mags and institutional attiiations\n", "Author details\n10\n", "Procome research groun Medical Management Cere, Depament of\nLeaning, infomatics, Management and Ethics Karolinska nstitutet, SE 171\n77 Stockhoim, Sweden. \"Unt for implementation and evaluation, Cerner for\nEpidemiciogy and Community Medicine CES Stockholm Courty Counol\n", "SE 171 29 Stockholm, Sweden Depatmert of Medical and Health Scences\nDivision of Commurity Medicine, Linköping Uriversky. Lirkoping, Sweden.\nSchool of Health, Canre and Social Werare, Mikardalen University. Box 883.\n721 23 Vasters. Sweden\n", "References\n", "Tranelating research for evidence based pubic hesth: key concepts and\nfuture directiors, J Epidemial Commurity Health 2012 https:/dol.org/10\n1 136jech-2011-200038\nGrimshaw J. Ecces M, Lave 1 HI S. Squres Knowledge translation of\nresearch findngs Implement Sc. 201250\n3 Foy R. Saes A Wensing M, Aarans GA, Flottarp S, Kant et al\nImplemenitation science a reapprasal af our jaumal mkdan and scope\nImplement Sci 2015,101.\nCharleswarth CI, Meath TH Schwartz AL, McConnel KI Comparison of low\nvalue case in Medicaid vs commercialy insured populations AMA htem\nMod. 2016 176998-1004.\nPerylndem ReserdCommuncanon. Urnecessary tests and procecdues in\nthe heath care system: Whet physicens say about the problem the causes\nand the sokutions Results trom a national survey of physicans. 2014 mp\nwww.droosingwisely.orgwp-contentucloak/201S/04Firal-OroosingWisel\nSunvey-Reponad. Accessed 27 Feb 2018.\n6 Eshoug AG MCWilians M, Landon BE. The value af low-value ists AMA\n2013309775-6\n2 Schwartz AL, Landon BE. Elshaug AG. Chernew ME, McWilams MA.\nMeasuting low-vakue care in Medicare JAMA Imtern Med 2014174:\n1067-76.\nB Robert G Hariock. Wilams L Dsentanging heteric and realty: an\nIntermational Delphi study of factors and processes that facilitate the\nsuccessful implementation of decisions to decommission healthcare\nservices. Implemere Sei 20149123\nBhatia RS, Levinson W, Short 5, Pondnth C, Fric Shamji E, Kallewaard\nM, et al. Measuring the effect of Chaosing Wisely: an integrated\nframework to assess campaign impact on low-value care BMI Qual\nSaf. 2015,24.523-31.\n10. Nven 01 Mrikas KI. Holodinsky K Straus SE Hemmeigam BR Jefs LP. et a\nTowards understandng the deadopoon of lowvake dinical practices a\nScoping review MC Med 201513255.\n11. Parks AL OMaley PG From choosing wisely to practiong value-more to\nthe story. AMA Htem Med. 20161761571-2\n12 Prasad V, loannide 1 Eidence bused de-implementation for contracicted\nunproven, and aspring heakhcae practices Implement Sci. 201491.\n13. Newstrom W. The managemert of unieaming explodng the \"dean skate\"\nfalacy. Train Dev 1 19833736-9\n14. Rooshenas , Owen Smith A, Donovan 1, Halingwarth W. Implementing\ndisinvestment decsians in practice: a qualitative investigation of parient\nand cinican perspectives. Lancet. 2014384 S67.\n15 Hodgerts K Eishaug AG, Hiller E Whar courts and how tO count it\nphysicians' constructions of evidence in a disirwestment conteat Soc 5o\nMed. 201252191-9\n16 Rushmer R, Daies H. Uniearning in hesth care. Qual Saf Health Care 2004\n13 Suppl 210-15\n17, Watt AM Hiler E Braunack-Mayer AL Moss JR, Buchan H. Wale I et a The\nASTUTE health study protocot deliberative stakeholder engagements to\nirform implementatiorn approaches to healthcare disimvestment implemer\nSd. 2012:7101.\n18 Coronin-Cronberg S, Rby H Laverty AA Wachter PM Mlet CErgish\nNational Heakth Service's savings plan may have helped reduce the use of\nthree lowvalue procedures. Health Af 201534381-9.\n19. Schwartz AL, Chemew ME, Landon BE, MCWlams M. Changes in low\nvalue services in year 1 of the Medkare Poreer Accountable Care\nOrgankation Program, IAMA Intern Med 2015175 1815-25.\n20 Hasson H Durer A Blomberg S Sanimaki A Significance of sciontic ovidenc\nkn organizing ore processes I Heith Organ Manag 201630597-612\n" ]

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[ "Learn more biomedcentral.com/suemissions\n", "support for research data, including large and comples data types\ngold Open Access which fosters wider colaboration and incressed cttations\nmaimum visibiity for your remarch: over 10OM website views per year\n", "At BMC, research is alwaya in progres\n", "a consolidited framework for advancing implementation science\nImplement So 2009,450.\n3. Rycroft-Malone i Promoting acton on neseordh implementation in heath\nservices (PARIHSI. in: Rycroh-Malone . Buckrel T, editors. Models and\nframeworks for implementing evidence-besed practice Iriking evidence to\nction. Oelord Wikey Blackwet 2010 p. 109-36.\n4. Care , OConnor D, Michie S. Valdation of the theoretical domains\nframework for use in behaviour charge and impiementation research\nImplement Sol. 2012737.\ns. Baker DW, Cascem A, Raynoids PP, Gardner LA Schneider EC. Deagn and\nuse af performanoe measuses to decease low value services and achieve\nCnst-conscious care Ann Intern Med 201315SS-9\n6. Shesperd S. Adams R HI A, Ganer S. Dopson S. Chalenges to using\nevidence trom systematic reviews 10 stop inetfective pratice an interview\nSTudy JHeath Serv Res Polcy. 201 318 140-6\n7. Mason Di. Oreosing whehy. chinging dinicura patients, or policies JAMA\n2015,313657-8\n8. Daniels T, Wilms L Robinson S Spence K Tacking dsnvestment in heath\ncore services: the views of resource alocators in the Engish NHS, IHealth\nOrgan Marag 20132762-80\n9. Nien P, Raback K, Brostiom A, Ektrom PE, Creatures of habit accouring\nfor the role of habt in implementation iesearch on dinical behaviour\nchange. Impiement Sd. 2012753\n0 Becker KL. hdividual and orgarisaional unleaming diections for finre\nresearch Intemational. IOrgan Behav. 2006.9659-70.\n1 Nben P, Neher M, Elström PE. Gardner 8. Implementation of evidence\nbeserd practice from a lesrning perspective Worldviens Evid-Based Nurs\n201714192-9.\n2. Michie S van Stralen MM, West R The behavour change wheet a new\nmethod for charactertsing and designing behavicur change interventions\nImplemert So. 2011042.\n1. Neal DT, Waod W, Labrecque I5, Laly P. How do habits guide behaviar?\nPorceived and actual triggers of habks in daty ife JExp Soc Psychal. 2012;\n48490-E\n4. von Thiele Schwarz U. Hason K Aigrmert for achieving a healthy\norganicanion n: Bauer GF, Jerny Gl, edtors Sautogenic organienions and\nchange Dordrecht Sprnger, 2013 p 107-25\n5 Wood W, Tam L Witt MG Charginrg cicumstances, dsrupting habits Pers\nSoc Prychol. 2005 918-33.\n6. Ezer 1 Social noms and economic theory. J Econ Perspect 1988199-117.\n7 Aarons GA Sommerield DH Leadership, innovation cimate, and attitudes\ntoward evidence based practice during a statewide implementation. 1 Am\nAcad Child Adolesc Paychiatry. 201251423-31\n8 McCormack & KiTson A Harvey G Rycot-Malone Trchen A, Seers K\nGetting evidence into practice: the meaning of conter. J Adv Nurs. 2002:\n3894-104\n9. Amotrong R, Hal B, Doyle Waters E Scopng the scope'of a cochrane\nreview. J Puble Heelth 2011:33147-50\nTong A, Sarabury P, Crag 1 Consoidated cnteria for reparting quaktative\nreseatch CORE: a 32tem checkist for interviews and focus groups ht i\nQual Heslth Care 200,19349-57.\n1. Fereday 1, Mur-Cochrane E Demanstrating rigor using thematic analysis a\nhytrid anproach of inductive and deductive coding and theme\ndevelopment. Int JQual Methock. 20nas 80-92.\n2 The National Board of Health and Weitare National Guidelines 2018 Po/\nwww.sociaktyreisen senionalguidelines Accessed 26 Feb 2018\n3. Czamiawoka-oerges 8. Shadowing and other techniques for doing\nfieldwork in moden societies. Copenhagern LiberCopenhagen Business\nSchool Press 2007.\n4 Mazzocato P, Forsberg HH von Thiele Schwarz U. Team behaviors in\nemergency care a qualkative study uning behavior analysis of what makes\nteam work. Scand i Trama Resusc Emerg Med. 2011,1970\ns. Hassan H, Blomberg 5 Duner A. Fidelity and moderating factor in complex\ninterventions a case study of a continuum of care progiam for fal elderly\npeople in health and social care. Implement Sci 2012,721.\n6. Brken SA, Poweeli BA Shes CM, Haires ER, Kik MA Leeman L. Rohweder G\nDamschroder L Pesseau Criteria for selecting implementation scence\ntheores and trameworks resuts fom an intemational gurvey Imolement\n" ]

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