The origin of genes is one of the most enigmatic events in the origin of life. It has been suggested that noncoding (nc) RNA was probably a precursor in the formation of the first polypeptide, and also at the origin of the first manifestation of life and genes. ncRNAs are also becoming central for understanding gene expression and silencing. Indeed, before the discovery of ncRNAs, proteins were viewed as the major molecules in the regulation of gene expression and gene silencing; however, recent findings suggest that ncRNA also plays an important role in gene expression. Reverse transcription of RNA viruses and their integration into the genome of eukaryotes and also their relationship with the ncRNA suggest that their origin is basal in genome evolution, and also probably constitute the first mechanism of gene regulation. I am to review the different roles of ncRNAs in the framework of gene evolution, as well as the importance of ncRNAs and viruses in the epigenesis and in the non-Mendelian model of heredity and evolution. The origin of genes, the genetic code and the genetic program, are puzzling events in the origin of life. At present, we know that in the genome of eukaryotic organisms there are different regions. Scattered throughout the genome are the regions of DNA coding for proteins, which in humans corresponds to approximately 2% of the genome. In the remaining 98%, the retroviral genes and also broad segments of DNA that code for non-coding (nc) RNAs are located.et al. in 1944 that the DNA corresponded to the hereditary material, the focus was mainly on the DNA as the central molecule in the hereditary models. This concept was consolidated as the Central Dogma of Molecular Biology [Once it was established by Avery Escherichia coli [At the dawn of genetics as an experimental science, the Mendelian gene was considered a symbol and a fixed and discrete heritable trait, indivisible by recombination, a concept that changed between the years 1955–1959 with Seymour Benzer’s studies on T4 phages in hia coli ,3. BenzeDrosophila melanogaster, and in rice about 15,000 genes more than human have been described. There are discrepancies between the number of coding genes and the size of the genome, these paradoxical facts are explained because the more variable and abundant regions are located in the non-coding regions. Thus, the proteomes of the higher organisms are relatively stable; humans and mice share 99% of protein coding genes and between human and chimpanzee structural genes show 98% similarity [With the first DNA sequencing effort by Frederick Sanger, it was clearly demonstrated that the gene is a nucleotide sequence that encodes proteins, in which genes encode for the amino acid sequence of the primary structure of proteins . Before milarity . TherefoAccording to a holistic concept, a gene is a useful sequence of nucleotides. Repeated sections of non coding DNA involved in the formation of centromeres, telomeres and replication origins should be called also genes –10. AlsoGenes were considered a continuous segment of nucleotides, until 1977 when Roberts and Sharp found that adenovirus transcribed RNA was fractionated into separate segments showing that genes are split into exons and introns. Later, in 1989, Thomas Cech and Sidney Altman discovered the catalytic properties of RNAs. They found that group I introns can be excised in the absence of any proteins acting as an enzyme (ribozyme).The discovery of ribozymes not only changed the central position of the DNA in the dogma of molecular biology but also the paradigm that DNA was the precursor molecules of life, and spurred the idea of a primitive RNA world . This hyThese ncRNAs, together with DNA methylation and acetylation of histones, are epigenetic factors that have changed the understanding of genome structure, the concept of the gene, regulation of gene expression and the mechanisms that account for organic evolution. The questions that arise are: what is the origin of ncRNAs? What is the relationship between ncRNAs with transposable genetic elements and viruses? What impact have they had on the legacy and evolution of species? And, should viruses be considered as a fourth domain? This article aims to answer these questions.The first ncRNAs were detected by Robert and Sharp in 1977 as micro (mi) RNAs during the discovering that structural genes were split into exons and introns. At first it was thought that introns have no function. However, since the discovery of messenger RNA splicing in adenoviruses , the altCaenorhabditis elegans when it was found that small miRNAs (constituted of about 22 nucleotides) were important for the appropriate timing of post-embryonic development [The first ncRNAs with a function were described in 1993 in elopment ,19. Actuelopment . Recentlelopment –23. One elopment  and thenelopment .Another hypothesis suggests that the first introns probably originated about 3500 million years ago in eubacteria and were restricted to tRNAs, and were mobile and self-splicing. From these spliced introns would have evolved spliceosomal from a common ancestor of eucaryotes and archaebacteria about 1700 million years ago with the origin of the nucleus and after the origin of mitochondria . SurprisSimilar sequences have been described between reverse transcriptase viruses, transposable elements, and mitochondrial introns . SimilarThe discovery of viroids by Diener  led to tIn mammals, many miRNAs derive from repeat elements such as LINES and Alu –38. Alu The resemblance of these ribozymes in viruses and also in organism belonging to the three domains of life suggests horizontal gene transfer. For example, the similarity of some vertebrate ribozymes with those widespread within mobile genetic elements in trematodes suggests that recurrent genetic horizontal transfers could have taken place from parasites to hosts .In recent years a wealth of information has accumulated about ncRNAs. They are characterized according to their function, location, length and also in relation with nearest structural genes. The non-coding RNAs have roles in a great variety of processes, including transcriptional regulation, chromosome replication, mRNA processing and modification, mRNA stability and translation, sex determination and even protein degradation and viral defense –41. For cis or trans. Trans-acting functions are associated with shorts ncRNAs (18–300 nt), such as siRNAs, micro (mi) RNAs, piwi-interacting(pi)RNAs and short nucleorar (sno)RNAs. Some miRNAs having both oncogenic and tumor-suppressive functions are dysregulated in many types of cancer. miRNAs also interfere with metastasis, apoptosis and invasiveness of cancer cells. [When their function is known, ncRNAs can also be classified by whether they act in r cells. ,40,43,44r cells. ,46. Endor cells. .Viruses can also generate viral miRNAs that disturb normal host cell functions. About 20–25% of human cancers have a known viral etiology. Expression of the viral oncogenes are regulated by alternative RNA splicing and several species of mRNAs can be derived from a primary transcript of a single viral oncogene to encode different oncoprotein ,48,43. Acis- acting functions have so far only been associated with macro or long nc (lnc) RNAs, which can be up to several hundred or thousand nucleotides long, about 200–2800 nt [Xist gene in cis), [Hox genes, in genome imprinting and as enhancers of gene expression [In opposition, –2800 nt ,51. In tin cis), , regulatpression ,53–56. Lpression –60.The concept of epigenesis was born to oppose the theory of preformism. This term was coined in 1942 by Conrad H. Waddigton to explain how an adult can be formed from a zygote, through development, by cell differentiation and gene regulation. The epigenesis is defined as heritable changes in the expression of genes that do not involve a change in DNA sequence but only changes in the chromatin. These changes alter the ability of genes to respond to external signals . Thus epC. elegans, miRNAs can function to prevent cell division and drive terminal differentiation. An implication of this hypothesis is that down regulation of some miRNAs might play a causal role in the generation or maintenance of tumors [In recent years, growing evidence has emerged that non-coding RNAs play essential roles in the regulation of gene expression in plants and animals, vertebrates and invertebrates ,63,64. Mf tumors .Trypanosoma mitochondria. A number of genes are expressed in an unconventional manner, the nucleotide sequence of primary transcripts is modified post-transcriptionally through the insertion or deletion of Uridine. These nucleotide alteration was coined as RNA editing [The concept of epigenesis also extends to DNA and RNA editing. RNA editing is an epigenetic regulatory mechanism that was discovered from the unicellular protozoa  editing ,67. RNA  editing –72. In h editing ,71. In m editing .RNA editing expands the possibilities for expression of the epigenome by the production of different proteins from a single structural gene . The RNAThe epigenome is also very important for genomic imprinting consisting in an asymmetric expression of genes with different paternal origins. Thus, genes are silenced when inherited via sperm or via egg. The term is used in relation to genes that are maternal inherited but silenced when paternally inherited. Thus, genomic imprinting is an epigenetic mechanism that induces parental specific gene expression in diploid eukaryotic cells ,77. The Genomic imprinting changes gene expression between parents without altering DNA sequence. However, these DNA sequences are crucial to score an imprinting domain that are composed of non-coding DNA sequences. The missing of these sequences implies the lost of genome imprinting ,64. NcRNMuch evidence has accumulated showing that imprinted genes can influence animal behavior. A paradigm in this way in humans are the Angelman and Prader-Willi syndromes that included neuroendocrine problems. Thus, children who inherit a deletion on chromosome 15 in the same locus from their father show a behavior different from these children that inherit these same altered locus from their mother . Also inRNA viruses have a simple organization. They carry short RNA sequences, which are surrounded only by a protein or lipoprotein capsule and do not have a metabolic system that allows them to reproduce itself autonomously. Indeed they do need the host for full metabolic activity. Viroids and virusoids are even simpler because the RNA is devoid of lipids and proteins and has no information for encoding proteins, and their genomes are similar in a conserved sequence to group I of introns that are found in nuclear rRNA genes, mitochondrial mRNA, rRNA genes, and chloroplast tRNA genes. The hallmark of these elements is a 16 nucleotide phyllogenetically conserved RNA sequence .According to their structure, viruses are more similar to a set of molecules than with an organism, placing them among the living and the nonliving. However, viruses have a hereditary material, an universal genetic code and structural genes similar to bacteria, archaea and eukarya, but they have not been considered in the origin of the first life-forms on our planet, nor as a domain in the tree of life. One reason is the dependence of the metabolic system of a host cell for their survival and reproduction. Additional evidence for not having a “virus domain” includes the idea that viruses are derived from the genome of eukaryotes, and have a very unstable genome . All thiViruses can recombine their genetic material with each other as was classically demonstrated by Benzer ,3 using Genetic recombination is a universal phenomenon in all living systems and is also one of the fundamental conditions of sexuality. In the most simplistic sense, sexuality is the transfer and recombination of genetic material between organisms of a species. From this point of view, sexuality occurs between the genetic material of different strains of viruses and also between viruses and the genetic material of their hosts.Salmonella typhimurium [E. coli K12 strain. In this case, λ is inserted between the gal and biotin genes, where it is as a prophage, but when it disintegrates the host genome gal of K12 gene it is part of the DNA of the virus and can be transduced to a different strain of bacteria lacking this gene when infected by the virus. In generalized transduction viruses prophages are inserted anywhere along the genome and can transduce any gene of the host. An example of generalized transduction is what happens in lysogenic strains of Salmonella typhimurium attacked by phage P22 [Classically it has been demonstrated that viruses may be intermediaries in the sexuality of strains of himurium . The mathimurium . Such tyhage P22 .Saccharomyces cerevisiae, recombination between retrotransposons is a source of chromosome rearrangements and a mechanism of genome evolution in this specie [Horizontal gene transfer mediated by viruses and bacteria have been detected in eukaryotes. In s specie . Recent s specie . Extensis specie .In particular, the persistent endogenous retroviruses in a long evolutionary time scale on a specific host can explain the origin of numerous basic and highly complex functions of life such as the origin of DNA-based genomes and DNA replication, eukaryotic nucleus, adaptative immune system and interference RNAs and mammalian placenta and viviparous birth ,98 and aThe affinity in terms of molecular structure, transmission and recombination of genetic material between viruses, transposons, and introns demonstrates the viral origin of the latter elements and strengthen the hypothesis of an initial world of RNAs. It is known that many retrotransposons and retroviruses differ only in the absence of a capsule. I concord with the idea that RNAs viruses should be seen as the first manifestations of life which culminated in the biochemical evolution in a naked RNA world that preceded the origin of the first cells. With the discovery of the ncRNAs and ribozymes, these were located in the center of the central dogma of molecular biology displacing the DNA. The most plausible hypothesis now in the emergence of the first molecules pioneers that life revolves around an RNA virus not dependent of DNA in their replication. Many of the functions within living cells such as replication, transcription and repair as well as their fine-tuned regulatory order are now known to also be of viral origin ,99.If the origin of introns and retrotransposable elements are viral, then ncRNAs, in base to its homology with these elements, have also a viral origin and are part of the genome in the different species of the tree of life. Thus, the ncRNAs, in the form of introns, by splicing of mRNA, regulates the genetic expression. Also, the other forms of small and ncRNAs, coded in the redundant DNA and located between structural genes, have many important roles in the organism.The molecular evidence demonstrates that the ncRNAs are scattered in the species that constitute the three domains of the tree of life. These ncRNAs are endosymbiont coadapted molecules with the genome of hosts and are the product of molecular coevolution from the origins of the first cells. The importance of RNA and DNA viruses in the evolution of their host as a persistent evolutionary force has been analyzed extensively by Villarreal ,98, thisThe natural viral transduction between the species that constitute the tree of life and genetic homologies between distant organisms suggest that the genome of living organisms, particularly multicellular is a “fluid mosaics of genetic information from different sources” . This faThe discovery of ncRNAs has represented a major shift in the way of conceiving genetic variation in natural populations. Before the advent of the ncRNAs, the norm of reaction and phenotypic plasticity were considered adaptive but it was thought they had no a hereditary basis. But, now we know that these phenomena have a strong epigenetic base and can be inherited, explaining the emergence of morphological adaptations such as camouflage and mimicry. The epigenesis may also explain the variation and heredity of complex traits and diseases in humans .According to Lynn Margulis the most important force in organic evolution is the endosymbiosis where bacteria have played a fundamental role in the origin of mitochondria and the chloroplasts. But, the roles of ncRNAs, their relation to RNA viruses embedded in the genome of species belonging to the three domains of the tree of life show that the endosymbiotic model must be extended to viruses. The phylogenetic analysis of relationships between RNA virus sequences and their hosts reveal coespeciation, products of thousands of years of ecological interaction between them. For these reasons it is necessary that the study of genome evolution, including human evolution, must include viruses and other parasites that also evolved from the same environments .


In contrast to the adult, the third-trimester foetus experiences one of the most intense periods of growth and maturation of its lifetime. Early development is characterized by the existence of critical periods when environmental factors effectively produce long-lasting changes.Proliferative retinopathy of prematurity (ROP) is a potentially blinding disease characterized by uncontrolled retinal angiogenesis. This pathologic angiogenesis is the target for two new treatment modalities for ROP, i.e. intravitreal anti-VEGF (bevacizumab) and systemic propranolol, which are being evaluated in ongoing or planned studies. VEGF is essential for normal angiogenesis in a growing infant, and the adrenergic system is important for many organ systems and, in addition, for plasticity of the visual and olfactory systems.This viewpoint raises concerns regarding the currently studied antiangiogenetic treatments for ROP and their possible general effects on the developing preterm infant. In contrast to the adult, the third-trimester foetus experiences one of the most intense periods of growth and maturation of its lifetime. Early development is characterized by the existence of critical periods when environmental factors effectively produce long-lasting changes. An example is that of the antiangiogenetic substance thalidomide, which during a very limited time period in early pregnancy causes gross malformations. Angiogenesis is important for the alveolarization of the lungs, which in humans mainly takes place after birth in infants born at term , and in The very preterm infant has lost nutrients and other factors supplied by the mother and is exposed to poor nutrition, hyperoxia/hypoxia, infections and other stresses resulting in impaired growth and development. In the eye, reduced physiologic angiogenesis may lead to hypoxia followed by uncontrolled vessel growth. This pathologic angiogenesis is the target for two new treatment modalities for retinopathy of prematurity (ROP), which are being evaluated in ongoing or planned studies. We would like to express our concern about possible adverse effects of these medications on the development of these vulnerable infants.In the Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity (BLOCK-ROP) study , intravitreal injection of 0.625 or 0.75 bevacizumab (Avastin®), an anti-VEGF antibody, will be compared with standard of care laser for type 1 prethreshold ROP diagnosed at 30–36 postmenstrual weeks. In the Safety and Efficacy of propranolol in newborns with retinopathy of prematurity (PROP-ROP) study   (n = 150), infants with stage 3+ ROP were given bilateral intravitreal injections of 0.625 mg of Avastin® bilaterally (Propranolol has been found to be efficient in reducing the growth of infantile hemangiomas in a number of patients ,9, althoThe hypothesis of the PROP-ROP study is that in preterm infants with ROP, VEGF overexpression could be induced by beta2-adrenoreceptor stimulation and that propranolol, administered when ROP stage 2 is detected in zone II or III, could reduce the progression of the disease. As mentioned by the authors, most cases of ROP stage 2 regress spontaneously, which means that most of the infants treated with propranolol never risked blindness anyway.Propranolol is reported to be well tolerated in most cases. However, hemodynamic effects such as bradycardia and hypotension as well as metabolic effects such as hypoglycemia may be serious –13. In aLess is known about the roles of the adrenergic system and the beta-adrenergic receptors on the development of the premature infant's brain. In rats, OIR is induced by exposure to increased oxygen concentrations from birth to postnatal day 11 followed by room air for 7 days after which proliferative retinopathy, similar to human stage 3 ROP, is found . In the It is likely that during the period when pathologic angiogenesis is a threat to the eye, windows of susceptibility occur in other parts of the central nervous system, where adequate angiogenesis and development of neural and other tissues are essential for later normal function. Administering potent blockers of VEGF and of the adrenergic system during these periods may be deleterious. As long as we lack methods to explore how the growth and modulation of neuronal networks are orchestrated, medications that possibly alter these processes for the rest of life should be avoided. In preterm infants prone to abnormal brain development, it will be impossible to sort out adverse effects of these drugs. Laser ablation of the retina is not ideal, but its effects are restricted to the eye and it usually works well. Antiangiogenetic treatment might be indicated in serious cases when laser treatment has failed, but that is different from it being an alternative to laser. There might be a place for propranolol for pathologic vessels just like for severe hemangiomas, but its use as prophylaxis to prevent proliferative ROP during stage 2 like in the PROP-ROP study should be questioned. If Avastin® is further used in infants, monitoring of serum bevacizumab and exploration of its pharmacokinetics and effects on premature babies are needed.


Neurophenomenological (NP) methods integrate objective and subjective data in ways that retain the statistical power of established disciplines (like cognitive science) while embracing the value of first-person reports of experience. The present paper positions neurophenomenology as an approach that pulls from traditions of cognitive science but includes techniques that are challenging for cognitive science in some ways. A baseline study is reviewed for “lessons learned,” that is, the potential methodological improvements that will support advancements in understanding consciousness and cognition using neurophenomenology. These improvements, we suggest, include (1) addressing issues of interdisciplinarity by purposefully and systematically creating and maintaining shared mental models among research team members; (2) making sure that NP experiments include high standards of experimental design and execution to achieve variable control, reliability, generalizability, and replication of results; and (3) conceiving of phenomenological interview techniques as placing the impetus on the interviewer in interaction with the experimental subject. The tension of scientific exploration involves both push and pull; it launches outward, across seas or solar systems, and yet draws us inward, into the depths of Earth and of our own minds. The topics presented in this article balance on that tension, with reference to a study of the inner experience of the mind as it faces outward toward the expanse of space. More specifically, the aim is to critically evaluate neurophenomenological (NP) methods for studying first-person experiences. We describe the techniques used in a baseline study and highlight areas for methodological improvement that may be helpful in future NP research. The baseline study acts as a reference point from which recommendations for methodological improvements may be extrapolated, contributing to the refinement of neurophenomenology as an approach for studying human experience.After reviewing some of the context of the broader NP tradition, emphasizing its relationship to (and contrast from) other cognitive science methods , we present an overview of the baseline study (see Overview of the Baseline Experiment). The final section includes an outline of the key “lessons learned” about NP methodology in the baseline study.While the nature of human experience has been questioned since the time of Aristotle, there is still no consensus in the scientific community regarding methods to approach such inquiries. Neurophenomenology is one promising approach, as its core purpose is to connect research in the various fields that study experience in a manner that fully integrates first-person experiential accounts with third-person neuroscientific measurements. To achieve this goal neurophenomenology uses techniques from cognitive science, neuroscience, and philosophical phenomenology in an attempt to piece together a dynamic and inclusive picture.As its name implies, neurophenomenology blends data collection methods from neuroscience and phenomenology. Phenomenology is a diversified philosophical approach initiated in the twentieth century by Edmund Husserl. It was conceived as a descriptive and analytic study of consciousness, including aspects of intentionality (the directedness or “aboutness” feature of consciousness) and phenomenality . Philosophers in this philosophical tradition, like One of the objectives of experimental neurophenomenology is to bridge first-person experience and neurophysiological data . As a foThe phenomenological methods employed in NP studies derive from and simplify the methodology explicated by (1)Subjects (as well as experimenters) suspend their beliefs or theories about experience;(2)Subjects gain intimacy with the domain of investigation by reflectively focusing on how they are experiencing the stimulus;(3)Subjects offer descriptions that are then intersubjectively validated.dynamic reciprocal constraints (DRCs) to illustrate this interplay of multi-source data. In the DRC model, constraints on data come, not from an externalized assumption of objectivity, but from a co-regulated interaction of subjective experiential reports and analyses of neurophysiological data. DRC distinguishes neurophenomenology from other approaches to handling first-person data by establishing a model that captures the interaction of scientist and experimental subjects.One important aspect of NP method is the avoidance of pre-defined categories. This correlates with the emphasis on first-person report and the suspension of theories. It reflects the attempt to stay with the subject’s experience without imposing external criteria or concepts, or assuming that we already know what such experience is like. In On the one hand, in contrast to DRC, in many cognitive scientific studies first-person data will be collected in the form of pre-defined scales and surveys. Less typically, participants may be interviewed, but every participant would be exposed to identical questions. Of course, these are legitimate scientific practices, as cognitive science attempts to attribute any variation in behavior to either experimental manipulations or individual differences. Researchers seek to control the parameters to draw strong conclusions about the influence of external factors on individuals. Such studies analyze data over identical conditions applied to diverse participants, but in so doing, they risk overlooking important aspects of experience such as attentive states, emergent distractive thoughts, or individual cognitive strategies.On the other hand, the particular NP paradigm proposed by Varela and used in the In this same spirit of widening the scope of neurophenomenology, First-person data inevitably pose large philosophical problems for empirical science, and these problems are manifest in two philosophical challenges to NP. One challenge involves reductionism, which is the proposition that explanations of consciousness and cognition can be reduced to purely physiological explanations, thereby eliminating the need to talk about first-person experience. The other challenge concerns sufficiency; it questions the capability of neurophenomenology to deliver on its promises to reveal anything that traditional scientific methods cannot capture.what there is must not omit those things that are not quantifiable or exclude those phenomena that involve extra-neural factors . The baseline study attempted to replicate and understand these experiences by placing subjects in simulated space-travel environments, recording neurological data  and physiological data (using ECG), and correlated first-person experiences .something bigger “out there.” Second, they experience something that few other humans experience, extraterrestrial space. This is not to deny, of course, that there are numerous experiences that could elicit AWCH here on earth .For the purpose of the baseline study, the researchers examined the constructs of AWCH. AWCH recur in the experiential accounts collected from astronauts’ (including cosmonauts’) journals and interviews. The astronauts’ narratives carry a unique power for many reasons. First, their demographics consist largely of scientists. Some significant number of them return from the experience of spaceflight changed, and some of their reports indicate that these changes are spiritual in nature. They report being moved affectively in a manner they describe as eliciting an internal change. They return to earth with a sense of In the past decade, scientists have promoted the cultivation of awe as a beneficial characteristic for clinical psychology and other areas of patient care. This perspective comes out of a larger movement that embraces an interdisciplinary approach to studying religious and spiritual experience more broadly. The larger project, as To explore the interdisciplinary challenges inherent to NP examinations of spiritual and esthetic experiences in any useful way, it is essential to narrow the focus and establish a shared nomenclature. In the research examined herein, awe and wonder provide construct exemplars. Awe, as a component of spiritual and religious experience, has been discussed in historic philosophical traditions. In the eighteenth century, Edmund Burke’s philosophical treatises struggle with the sublime and beautiful, binding these constructs conceptually with awe-filled emotions. These emotions do not imply pleasure, in its most obvious sense, but awe as a direct and initial feeling when faced with something incomprehensible or sublime. In contrast to the directness of awe, wonder demands cognitive reflection. Curiosity, also involves a desire to piece things together, but in a different way. Curiosity involves wanting to know, see, experience, and/or understand more . The Bildakt analyses revealed necessary requirements for the images used in the simulation including characteristics of photograph quality and image angle and perspective. With these conditions in mind, the team designed a set for a mixed-reality simulation wherein participants were immersed in the sounds and visuals resembling something like a science fiction movie set.The baseline experiment was part of a collaborative interdisciplinary project entitled Bildakt analyses (listed above) reflect an intention to increase immersion, clarify point-of-view, and be applicable to the limitations of the mixed-reality simulation environment used in the experiment.Both the baseline study and other experiments in this project used simulation technologies to generate controlled conditions. Varying degrees of realistic experiences are possible within virtual reality simulators and they can allow for NP research to be conducted with high levels of control . To estaAspects of context were incorporated into the simulation design and were crucial in the experimental strategy. All participants experienced identical “launch” context narratives and were placed in the same physical environment. Although the contextual cues for all participants were objectively identical, the experienced context varied due to a variety of factors, including the participant’s background and their current bodily state. In all research, contextual circumstances, both objective and subjective, contribute to the experience. Context consists of any information or factor that can be used to characterize the circumstances or situation of the participant. Multiple factors might be relevant to the interaction between a participant and the simulation and may or may not be manifest within the simulation itself; in this regard, the participant determines the perception and experience of relevancy. In basic NP research, this means that control of contextual variables within the experimental environment is of utmost importance.The baseline study applied these principles of simulation context design in the development of the mixed-reality simulator and the conditions presented therein. The experimenters presented the study to participants in terms of simulated space travel and worked to support the narrative that reinforced the idea that the participant had been selected to have the unique opportunity for virtual space travel. The experimenters worked to maintain the story narrative of an impending launch, even while placing neurophysiological sensors on the participant.Researchers collected real-time physiological and neurophysiological measurements using EEG, ECG, and fNIR while the participants were immersed in the mixed-reality environment and observed the space scenes. The experimenter sat unseen by the participant, outside of the space vehicle and could only be contacted through radio control.After “suiting up” with the various physiological and neurophysiological monitors, the participant was in the mixed-reality environment which resembled the interior of a space vehicle . The participant then, after a short delay, experienced a launch sequence , followed by silence. Once the participant was “in space” large computer monitors embedded in the walls of the space vehicle opened virtual portals revealing dynamic images of space, including views of Earth, Moon, the International Space Station, and expanses of stars. After the participant viewed the images, the space vehicle “returned to earth” (relayed to the participant through radio control) and the participant answered brief questionnaires, repeating some of the questions that had been asked previously and introducing questions of workload. Experimenters removed all sensors and then brought the participant to meet an interviewer. The interviewers were philosophy graduate students trained in phenomenological interview techniques. Interviewers escorted participants to another area for interviewing, with the succinct goal of exploring the participant’s experience during the simulated space flight.From the beginning to the end, the baseline experiment was executed much like a relay race, with researchers passing the baton from one stage of the experiment to the next. The analysis of the collected data required a division of labor by the various contributing disciplines. Human factors psychology and neuroscience experts examined the data from the psychological and neurophysiological measurements. Phenomenologists reviewed the transcripts and recordings of the interviews and conducted linguistic and hermeneutical analyses. The latter was informed by a previous analysis of the astronaut journals that provided 37 categories reflecting AWCH experiences. That starting point was leveraged for a comparative evaluation of the participant interviews. The results showed promise. For example, in preliminary analyses, the results of the neurophysiological data indicated engagement of frontal lobes during the feeling of wonder and parietal lobes during physical affect. Participants who reported experiencing awe, wonder, religiousness, or spirituality were compared to those who did not indicate such experiences. Neural activity varied significantly between experiencers and non-experiencers and was greater for the Earth view than the Deep Space view. In addition, participants who reported higher levels of religiousness (as indicated in the questionnaires) were more likely to report awe and wonder when viewing the Earth (as opposed to only stars).The results did not lack merit. To the contrary, the results provided information about human phenomena that otherwise have garnered little empirical exploration to date. The results of the baseline experiment contribute to a compelling case in favor of further exploration using neurophenomenology. The work supports the application of open-ended interviews for a broader range of basic-research contexts. However, the experiment provides “lessons learned” for improving NP methods in hopes of generating more conclusive results.Neurophenomenological experimentation must purposefully and systematically include the creation and maintenance of shared mental model (SMM).Neurophenomenological research must embrace systematic and thorough creation of SMMs as part of the neurophenomenology as applied philosophy in the research world. Its intrinsically interdisciplinary nature demands that contributing domain experts avoid the “passing the baton” approach that can result in a mere collection of data in a non-contextualized way . Each paNeurophenomenological experimentation should be held to the high standards of experimental design and execution to achieve variable control, reliability, generalizability, and replication of results.In the complexities of carrying out an interdisciplinary study with multiple parts, problems can arise. In the baseline study, there were many possible variables that could have explained components of the experience . It was therefore impossible to conclusively determine which manipulations generated the various aspects of the experiences. In part, this problem in the baseline study was the result of inadequate SMMs mentioned above. Team members, working within the confines of their own specialized disciplines were not always able to see the whole picture, and this had an effect on the overall design of the experiment. This, of course, is not inevitable, or necessarily a characteristic of other NP experiments, but that this problem did characterize the baseline study suggests that adopting different practices is something that needs to be made explicit. Accordingly, the second methodological lesson is a reminder that psychology and the cognitive sciences already have a time-tested tradition of precision in experimentation and that neurophenomenology can benefit from attending to many of the practices involved in this tradition.As researchers design a NP experiment, they should consider many of the questions that their counterparts in traditional cognitive science might ask. For example, does it make sense to generalize first-person data? Cognitive scientists, with a firm footing in psychology, consider the extent to which any finding can be generalized to the population at large, and that consideration may affect the manner in which the data is both collected and handled. Neurophenomenologists need to grapple with that question as well, and avoid oversimplification of the factors that contribute to the results.In addition to generalizability, cognitive psychology also considers verification. A well-formed NP study needs to consider procedures for the verification of subjective experience. The baseline study, due to the length of experimental sessions and the uniqueness of using the NP approach, only included one aspect from each field that compose neurophenomenology. In other words, neurological and physiological measures from neuroscience were used to assess one part of the participants’ experience , questionnaires from psychology were used to assess another part of the participants’ experience , and phenomenological interviews from philosophy assess participants’ linguistic attribution of their experience in the environment as though they were reliving the experience. There was no overlap; no checks and balances. Strictly, this was a neurophenomenology study, but not an optimal application of NP methods, which thereby limit the power of the interpretation of the results. Again, to iterate, the data attained from the baseline experiment is useful and informative to the phenomenon under investigation as seen from each discipline, but perhaps short of the ideal of neurophenomenology.Depending on the study, other disciplines can provide complementary tools for verification. On its own, a Likert scale of self-reported affect (a tool from psychology) will not capture lived experience. However, it can provide correlations and comparisons that can provide verification when interpreting the findings from the phenomenological interviews. When designing the experiment, researchers can incorporate established methods from psychology, taking care to avoid influencing the phenomenological interview. For example, a sliding qualitative scale of affect can be given after the phenomenological interview. The information from the scale can provide support to the textual analyses of the interviews. The scale cannot, on its own, capture unique lived experience, but it can add credence to the basic findings in neurophenomenology.In regard to using methods from cognitive science, researchers designing NP experiments must also consider the replicability of their experiments. For example, neurophenomenology has been used to explore experience in epileptic preictal states . In thisTo do this, the experimental design might include the embracing of simulation technology. Simulation test beds allow for high variable control and precise stimulus/response recordings, consequently increasing successful replication. Simulations can be shared between institutions, permitting more diverse population testing . For example, future experiments in our project will use a portable simulation environment. This form of immersive simulation allows the presentation to be packed up and taken to another location, so that other locales can benefit from the technique. It also is a straightforward, and relatively cost-effective form of simulation presentation, so that laboratories with limited simulator resources can erect similar systems. A digitally controlled presentation of experimental stimuli allows for improved generalizability, replicability, and verification, and can thereby give more credence and credibility to the NP findings. Interplay between the phenomenological project and some techniques of cognitive science can generate a unique integrative methodology. As such, neurophenomenology should take the best of the practices of cognitive science, while contributing its unique techniques that have not been a common part of the cognitive science toolbox.The phenomenological interview places the impetus for training on the interviewer, not the participant, so that the interviewer may act to support the participant in precise experiential reporting.The third lesson to extract from the baseline study is that the real question of phenomenological training should shift from focusing on the participant to the interviewer.participates in the reflection and articulation of experience. This participation on the part of the interviewer is a marked difference from the objective techniques of cognitive science and as such, has potential for opening forms of data collection and analyses of experience that have not yet been fully explored.Though Lesson #2 argued for the importance of adopting specific practices from cognitive science, Lesson #3 involves the aspect of neurophenomenology that stands in contrast to cognitive science. To work through the argument, it is essential to first describe the role of training in the interview. The “training trade-off” depicts how the line between the interviewer and interviewee can dissolve, so that the interviewer actually As discussed above, much NP research has been based on the idea that only a person trained in introspective or phenomenological techniques can provide details with the degree of precision required for meaningful results cf. . PetitmeThe impact on methodology is that the emphasis shifts from a question about the degree of training a participant does or does not receive. This degree of self-awareness cannot be controlled in participants with the interview approach. Instead, the onus for training is directed toward the interviewer. The training trade-off is compensatory, in that the interviewer’s skill will improve the chances of the untrained participant’s successful articulation of her experience. If the interviewer is working with Buddhist monks, she may not need to receive a great deal of training and may be able to simply tell the participant the focus of the study. Conversely, if the same interviewer is working with undergrads at any given university in the West, she may need to pull from a collection of tools and techniques to give the participant the capacity to access the thoughts and feelings experienced.It should be noted that, while the training trade-off is presented, primarily as a methodological lesson, it has important theoretical weight as well. This dynamic between interviewer and participant has value for the debate regarding phenomenological experimentation. The dynamic interaction demanded by the NP interview method is not part of traditional cognitive science. In the NP interview, there is a cognitive off-loading by the participant onto the interviewer that traditional psychology does not always recognize. The phenomenological interviewer has the power, if executed in the manner described herein, to do some of the cognitive work of focusing the participant precisely on the participant’s lived experience, a task that may be otherwise impossible for the untrained participant. This is not one of the tools of traditional cognitive psychology. When psychologists employ the similar technique of introspection (perhaps in therapeutic sessions like hypnosis), they involve actually training the participant to look inward. The goal, in such cases, is not to extrapolate a description of an experience itself. Rather, interview questions are tools used, perhaps by applied psychologists/therapists, but certainly not typically by basic researchers. When neurophenomenology employs the interview, it is a core method that is fundamentally part of the experimental approach, and as such it changes the way the first-person experiential data is captured and handled.This does not degrade the first-person experience, treating it as third-person data (as Consequently, the third lesson involves a “training trade-off” in integration of the interview into experimental design and execution. NP methods can work with this adjustment in focus from the participant to the interviewer, and the re-evaluation needed for each unique experiment. The interviewers can pull from multiple tools and techniques with the aim of eliciting the necessary acts of reflection and articulation. Reflecting on our own experiences in conducting a baseline study employing NP methods, we have explicated a number of problems that we encountered and made suggestions for addressing such problems. The first involves improving communication practices among research team members and establishing a shared understanding of the methods and goals of neurophenomenology. This is especially important since neurophenomenology involves certain ways of rethinking received scientific procedures and is not the standard approach in which many of the researchers have been trained. The second involves the importance of incorporating some of the best scientific practices into NP methods, especially those that involve control, reliability, generalizability, and replication. The third suggestion involves the use of a phenomenological interview technique and the question of who gets trained, and how. Each of these suggestions should be considered in the variable contexts of NP research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Migration is difficult to measure because it is highly repeatable. Health and Demographic Surveillance Systems (HDSSs) provide a unique opportunity to study migration as multiple episodes of migration are captured over time. A conceptual framework is needed to show the public health implications of migration.Research conducted in seven HDSS centres [International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) Network], published in a peer-reviewed volume in 2009, is summarised focussing on the age–sex profile of migrants, the relation between migration and livelihoods, and the impact of migration on health. This illustrates the conceptual structure of the implications of migration. The next phase is described, the Multi-centre Analysis of the Dynamics In Migration And Health (MADIMAH) project, consisting of workshops focussed on preparing data and conducting the analyses for comparative studies amongst HDSS centres in Africa and Asia. The focus here is on the (standardisation of) determinants of migration and the impact of migration on adult mortality.The findings in the volume showed a relatively regular age structure for migration among all HDSS centres. Furthermore, migration generally contributes to improved living conditions at the place of origin. However, there are potential negative consequences of migration on health. It was concluded that there is a need to compare results from multiple centres using uniform covariate definitions as well as longitudinal analysis techniques. This was the starting point for the on-going MADIMAH initiative, which has increased capacity at the participating HDSS centres to produce the required datasets and conduct the analyses.HDSS centres brought together within INDEPTH Network have already provided strong evidence of the potential negative consequences of migration on health, which contrast with the beneficial impacts of migration on livelihoods. Future comparative evidence using standardised tools will help design policies for mitigating the negative effects, and enhancing the positive effects, of migration on health. A migrant is a person who has established a new place of usual residence  other than the one in which they habitually lived . InternaMigration impacts on the place and household members left behind as well as on the place where migrants settle, in addition to creating a link between these two places among which people, information, and goods may flow. Migration is related to human capital (housing and family transitions) as well as to labour market conditions (economic opportunities at destination) . RemittaWith respect to the effects of migration on health, migration can induce stress  and in addition stress can be related to other health outcomes (e.g. reduced immunity) . MigratiLooking at the effects of health on migration, individuals and households may migrate, e.g. from a rural to an urban area to gain access to treatment for a specific condition or in general to be in a place where the overall availability and quality of health services are higher . ConversMigration is difficult to measure notably because it is highly repeatable . Migration research is largely based on data from censuses and surveys . While cThe conceptualisation of migration from a public health perspective can be challenging due to measurement difficulties and contradictory evidence. This article describes the conceptual framework used by the Migration, Urbanisation and Health Working Group of the INDEPTH Network when producing a peer-reviewed volume in 2009 on migration, livelihoods, and health. This led to a more systematic examination of these issues by means of more rigorous multi-centre comparative studies, which is also described. Examples are used from the volume to illustrate key concepts in the framework.The data presented in the INDEPTH volume with this title, published in 2009, show features of the positive and negative effects of migration from a public health perspective . The resDespite the diversity of contexts from which the data originated  and some variation in the threshold of time used to classify migration, a relatively regular age structure for migration was found . The larIn Matlab , findings on the association between parent’s migration and children’s education  indicateA study conducted in Agincourt  looked at the relationship between migration and household SES, especially focussing on the patterns and trends in remittances over the period 2000–2007 and the change in household SES . It was A study conducted in Kanchanaburi  examined how migration away from agricultural households is associated with changes in the amount of land used in cultivation and the amount of household labour employed in agriculture . It was In summary, these three studies have shown that migration, specifically out-migration from the origin HDSS community, generally contributes to improved living conditions at the place of origin.A study in FilaBavi  looked at the relation between migration and child morbidity, focussing on the association between migration and under-five morbidity . The regA study conducted in the informal settlements of Nairobi (urban Kenya) focussed on the effect of mother’s migration on childhood mortality . ChildreOn the other hand, a study conducted in Nyanza  showed that urban–rural child migration was significantly associated with a lower risk of death . ChildreHistorically, returning migrants were expected to be positively selected for health and economic situation, retiring with their earnings to the comfort of their home village and having a lower mortality than non-migrants. However, HIV/AIDS changed the situation, e.g. in South Africa, and migrants returning home could now be in poor health, needing care, and support from their families , 13. A sThus, the findings in the studies focussing on migration and morbidity/mortality highlight the potential negative consequences of migration on health which contrast with the beneficial impacts of migration on livelihoods.Although the book chapters give answers to the research questions posed, the results are from individual HDSS centres, addressing slightly different objectives, and using different definitions and analytic methods. The book concluded on the necessity to compare results from multiple centres using uniform covariate definitions as well as longitudinal analysis techniques. This was the starting point for the Multi-centre Analysis of the Dynamics In Migration And Health (MADIMAH) initiative.The aims of the INDEPTH MADIMAH project are to:  standardThe MADIMAH project focuses initially on the following two research questions:  What areEstablishing the determinants of migration is important for two reasons. Firstly, migration is a key socio-demographic event, and it is therefore important to identify its determinants at community, household, and individual levels. This has not been done systematically so far in HDSS centres, i.e. using the same definition of migration and determinants as well as the same analytical techniques. Secondly, if the impact of migration on mortality needs to be estimated, it is important to know the factors related to migration before to the move, because these may also be related to the risk of mortality.It is important to study the relation between migration and mortality for three main reasons. Mortality is a major indicator of health and one that is measured in all HDSS centres. Secondly, migration could be dependent on health status with the latter either impeding or stimulating migration. Thirdly, migration is usually conducted for economic benefits, which – as was seen in the book chapters and other publications , 13 – caThe MADIMAH project consists of a series of workshops focussed on preparing the data for a comparative analysis amongst HDSS centres in Africa and Asia to answer the posed research questions as well as to conduct the analysis. Training materials are developed and presented by experienced statisticians who have worked with data from multiple centres . These are used during the workshops and later on adapted (if needed) for future use in workshops or on-site guidelines for centres. In-between workshops, centres are assisted from a distance to finalise the research outputs.The first phase focussed on the dataset preparation and preparatory analyses. A 5-day workshop was held in April 2011 in Accra (Ghana) with 13 HDSS centres present. Objectives of the workshop were to:  check thIn October 2011, a second 3-day workshop was held in Maputo (Mozambique) with 14 HDSS centres. The training focussed on event history analysis  for migration, mortality, and fertility studies. The workshop outputs included: (www.indepth-ishare.org)  ; (2) proare.org)  preparinare.org)  producinIn February 2013, a 4-day analytical workshop was held in Nairobi (Kenya) on determinants of migration in 13 HDSS centres. Aims of this workshop were to standardise measures of migration and determinants and to do descriptive and longitudinal regression analyses of determinants of migration. This included the analysis of time-changing covariates such as education and union status  using Cox models. This will lead to publications on the determinants of migration by each centre as well as to multi-centre publications.Another workshop is planned towards the end of 2013 focussing on migration and mortality which will build further on the previous workshops and focus on the analysis of migration and mortality.The MADIMAH project has enabled efforts in standardisation of data preparation and analysis for studying migration in relation to the SES of the households and the health and wellbeing of migrants, especially in terms of mortality. A present limitation is that the current project cannot see what happens to out-migrants who have left the study population (which is similar to the problem of loss to follow-up in non-migration studies). To obtain this information, the routine of HDSS data collection should be complemented by follow-up surveys in the most common out-migration destinations to cover issues of changes in, e.g., health status and SES. Tests of follow-up through mobile phones 1 year after migration have been successfully conducted in three INDEPTH centres .It has been argued that HDSS centres are relatively expensive and their data take time to be collected and analysed. They are often underutilised in providing evidence for improving the health of the populations studied . The latIn conclusion, HDSS centres brought together within INDEPTH Network have already provided evidence for understanding the dynamics in migration and health. Further analyses using standardised tools are needed to build comparative evidence. This will potentially lead to adaptation of policies and targeting of interventions for mitigating the negative effects, and enhancing the positive effects, of migration on health.


Unmet health needs should be, in theory, a minor issue in Italy where a publicly funded and universally accessible health system exists. This, however, does not seem to be the case. Moreover, in the last two decades responsibilities for health care have been progressively decentralized to regional governments, which have differently organized health service delivery within their territories. Regional decision-making has affected the use of health care services, further increasing the existing geographical disparities in the access to care across the country. This study aims at comparing self-perceived unmet needs across Italian regions and assessing how the reported reasons - grouped into the categories of availability, accessibility and acceptability – vary geographically.Data from the 2006 Italian component of the European Union Statistics on Income and Living Conditions are employed to explore reasons and predictors of self-reported unmet medical needs among 45,175 Italian respondents aged 18 and over. Multivariate logistic regression models are used to determine adjusted rates for overall unmet medical needs and for each of the three categories of reasons.Results show that, overall, 6.9% of the Italian population stated having experienced at least one unmet medical need during the last 12 months. The unadjusted rates vary markedly across regions, thus resulting in a clear-cut north–south divide (4.6% in the North-East vs. 10.6% in the South). Among those reporting unmet medical needs, the leading reason was problems of accessibility related to cost or transportation (45.5%), followed by acceptability (26.4%) and availability due to the presence of too long waiting lists (21.4%). In the South, more than one out of two individuals with an unmet need refrained from seeing a physician due to economic reasons. In the northern regions, working and family responsibilities contribute relatively more to the underutilization of medical services. Logistic regression results suggest that some population groups are more vulnerable than others to experiencing unmet health needs and to reporting some categories of reasons. Adjusting for the predictors resulted in very few changes in the rank order of macro-area rates.Policies to address unmet health care needs should adopt a multidimensional approach and be tailored so as to consider such geographical heterogeneities. Servizio Sanitario Nazionale, SSN) is grounded on the Constitutional principles of universalism and comprehensiveness, many Italians still perceive that they do not receive the health care they require. One commonly used indicator of access to care is self-assessed unmet health care need. Compared to the prevailing approach in measuring access to health care, which is based on actual utilization , the use of subjective indicators allows not only to account for those perceived medical needs that do not turn into demand, but also to investigate the process of seeking medical care and the subjective barriers that individuals with health needs encounter in accessing it.Though the Italian National Health Service  which must be guaranteed nationwide. However, marked organizational differences exist in the way Regions have decided to accomplish their health delivering task, which could potentially result in different access rates and barriers to health services.The analysis of unmet medical needs at the regional level is particularly important in Italy where a progressive decentralisation process has been taking place since the 1990s, increasing the powers of Regional Health Authorities in both the financing and delivery of health care. Regions are now fully responsible to organize their health care systems so as to deliver the essential levels of care  that rely on a National Health Service but have decided to decentralize health responsibilities to lower levels of governments. For these countries, the existence of intra-country differences in unmet health needs and in the related reasons, further strengthen the choice to decentralize health care so as to better tailor health policy responses to local specificities. Outside Europe, other countries (e.g. Canada) with similar health system characteristics may show a similar interest in the empirical approach of this work. Finally, also for those countries where the health care system is highly centralized, it can be useful, for policy purposes, to investigate whether geographical differences exist in the prevalence of unmet needs and in the reported reasons.From a methodological point of view, compared to cross-country analyses, sub-national ones require less cautions in formulating conclusions, since unmeasured heterogeneity in the dataset due to cultural and health system differences can be better controlled for.Aziende Sanitarie Locali – ASLs). The actual SSN organizational structure is the result of a set of reforms undertaken since the early 1990s, aimed at introducing quasi-market mechanisms into the health system as well as at devolving new responsibilities for both the financing and delivering of health care to regions.Italy has a National Health Service which was established in 1978 to provide comprehensive health insurance coverage and uniform health benefits to all citizens and legal residents, throughout the country. The SSN is funded from general taxation and organized on the basis of a three-tier structure of government: central , regional  and local , decentralization of health care has been seen as a way to improve local responsiveness, promote participatory democracy, contain health expenditure and enhance efficiency. Regions are free to organize their health care services according to their local specificities but it is the central government’s responsibility to define and monitor the LEA services.In Italy, primary care is provided by independent contracted general practitioners (GPs) and pediatricians paid on a capitation basis that act as gatekeepers for the access to secondary services. Individuals may choose any physician they prefer, provided that the physician’s list has not reached the maximum number of allowed patients .Specialized ambulatory services, including visits and diagnostic and curative activities, are provided either by ASLs or by other public and accredited private facilities with which ASLs have made agreements and signed contracts. Patients are allowed to access specialist care only after approval by their GP, who is responsible for the referral. Once the GP has authorized the visit or the procedure, patients are free to choose any provider among those accredited by the SSN and any place of treatment.Depending on the region of residence, the payment of a user charge  is sometimes required as an additional source of financing and in an attempt to discourage an inappropriate use. Services for which a co-payment is required include ambulatory treatments, diagnostic and laboratory tests, specialist care, drugs, medical appliances and glasses. Inpatient care and primary care are free at the point of use. In emergency cases, direct and free access is allowed for all health services. Nonetheless, cost-sharing exemptions are allowed for specific groups, depending on income, age, health conditions and other individual characteristics.Because of long waiting lists and the not always satisfactory quality of public services , many individuals often consult private outpatient specialists, at their own expense. As in other European countries , with increasing personal income levels, individuals often opt to supplement their public health insurance with the purchase of private insurance and/or private services. Although the utilization of private health services differs greatly by region, in 2005 an average of about 5% of primary care visits, 57.2% of specialist visits and 21% of diagnostic services were entirely paid out of pocket by individuals [This study is based on data from the European Union Statistics on Income and Living Conditions (EU-SILC). Although the EU-SILC survey is mainly oriented to the analysis of poverty and deprivation, it also provides the opportunity to explore issues related to health accessibility: a set of items is specifically designed to measure self-assessed health status and barriers encountered by household members aged 16 and over in trying to access medical services.Istituto Nazionale di Statistica, ISTAT) through face-to-face interviews, comprises 21,499 households  who are selected from across the country, using a stratified two-stage sampling design. We restricted our analysis to adults aged 18 and older  since access to health care services by individuals under that age is generally tied to the decisions of their parents or legal guardians.The 2006 EU-SILC module for Italy, conducted by the National Institute of Statistics  could not afford to (too expensive); 2) too long waiting lists; 3) could not take time because of work, care for children or for others 4) too far to travel/no means of transportation; 5) fear of doctor/treatment; 6) wanted to wait and see if the problem got better on its own; 7) did not know any good doctor or specialist; 8) other reasons. Multiple responses were not allowed.Self-reported unmet medical need was defined on the basis of the following question: “During the last 12 months, was there ever a time when you felt you needed a visit by a specialist or a medical treatment but you did not receive it?”Following the previous literature on access barriers to health care services, answers were classified into four categories according to the nature of the stated reason: availability, accessibility, acceptability and other . The firIn an attempt to better disentangle the potential role played by policy makers in reducing unmet health needs, some authors ,20 have predisposing, enabling and need factors. Predisposing factors include socio-demographic variables and health beliefs that influence the propensity of individuals to seek health care. The predisposing variables used in this paper are age, sex, level of education, marital and activity status. Enabling factors include personal, family and community resources that can either facilitate or impede the use of health services. Hence, individuals were grouped into quintiles according to their equivalised annual disposable (i.e. after-tax) household income. The modified OECD equivalence scale was used, which gives a weight of 1.0 to the first adult in the household, 0.5 to the second and each subsequent person aged 14 and over, and 0.3 to each child aged under 14. Under the EU-SILC, household total disposable income includes all of the net monetary income received by the household and its members during the reference year - namely all income from work (employee wages and self-employment earnings), private income from investment and property, transfers between households plus all social transfers received directly including old-age pensions, net of any taxes and social contributions paid. No account is taken of indirect social transfers. Three measures of need are used in this study: 1) self-rated general health status ; 2) the presence of chronic conditions; 3) the presence of limitations in daily activities due to health problems.Potential predictors of unmet medical needs were selected according to the Andersen’s Behavioural Model of health service use . The modWe entered all of the above explanatory variables into multivariate logistic regression models for unmet needs overall and for the different typologies of reasons. Least squared means resulting from the models were used to determine adjusted rates. To simplify the sub-national analysis, the nineteen Italian regions and the two autonomous provinces were grouped into five macro-areas: North-West, North-East, Centre, South and Islands. Data were also weighted at individual level  to make the results representative for the Italian general population. Missing and partial information accounted for less than 0.5% of the total and were therefore dropped from the final sample . Robust estimators of variance that accounted for the effects of weighting were used -25.In 2006, approximately 6.9% of the Italian population aged 18 and older experienced at least one unmet need for health care over the past 12 months . Distribution of study population and self-perceived unmet medical needs by the predictor variables used in the multivariate logistic regression analyses are provided in Table As for the predisposing factors, with the only exception of availability, women were statistically more likely to report unmet needs for each category of reasons. The likelihood of experiencing any type of unmet medical need decreased with age. Except for few cases, the level of education did not appear to be significantly associated with unmet needs. Unmarried individuals were less likely to report unmet needs overall and needs due to accessibility problems , while the opposite seemed true for separated, divorced and widowed persons. Not surprisingly, activity status was found to be positively associated with the probability of remaining without care, especially because of not being able to take time off. Economically active people were much more likely to experience an unmet health need in general and to report an acceptability problem, in particular. With regard to the enabling factors, there was evidence of an income gradient. Other things being equal, individuals in the highest income quintile groups were less likely than those in the lowest ones to report unmet medical needs, particularly due to problems of accessibility. Health status showed a strong association with all of the reported reasons: people claiming to be in good or very good health were less likely to perceive any unmet medical need. Having any chronic condition also increased the likelihood of experiencing an unmet medical need, as did the fact of being hampered in daily activities because of health problems. Differences in the odds of unmet needs were observed among geographical areas. Independently of the stated reason, the odds of having experienced an unmet medical need were greater for people living in the South and the Islands than for those residing in the rest of the country. Except for the acceptability category, whose result was not statistically significant, people in the North-East had the lowest likelihood of reporting unmet medical needs.Unadjusted and adjusted rates of self-perceived unmet medical needs, overall and by category of reasons are reported by macro-area and compared in Table The empirical analysis suggests that, in spite of the SSN statutory obligation to provide equal access according to needs to all Italian citizens and legal residents - regardless of factors such as income, gender, ethnicity, education, religion and geographical location -, a certain percentage of the adult population claims that their health care needs are not met. This percentage is, however, not uniform across the country: there is evidence of marked regional variations in unmet needs overall and in the reported reasons. With very few exceptions, moving from the North to the South of the country, rates of self-perceived unmet medical needs increase and the stated reasons change. At the national level, cost of care is the most important reason reported for unmet health needs, followed by waiting lists and difficulties to reconcile the visits with work and family commitments. Consistent with its social and economic specificities, in the richer and more industrialized North competing priorities become a relatively more important motivation, albeit affordability is always the leading reason. On the contrary, in the South lack of financial means represents the sole relevant barrier to health need satisfaction. Here, work and family commitments are perceived as a minor problem, perhaps because of the lower employment rates, which make easier for individuals to take time off for seeking health care. Moreover, in these geographical areas a more extensive concept of family network exists, which helps women in their care-giving responsibilities, even in presence of worse-quality public services.In line with previous international studies ,13,16,18Some of the above findings require more in depth explanation. Gender differences in unmet needs can be due to the fact that women usually retain primary responsibilities as homemakers and family caregivers. These multiple roles generate more competing priorities and leave women with less time to seek care for themselves. However, the relationship between sex, health care use and unmet needs can also prove to work differently, though with the same final effect on unmet needs. Since women are more likely to be the primary care seekers for dependent children and elderly family members, they have generally more contacts with the health care system and, thus, more opportunities to experience difficulties in accessing care and, hence, to complain for unmet needs. As for age, prior studies suggest that expectations about the health care system may not be the same at different times in life -28. In pAdjusting for factors associated with unmet needs results in slight changes in the rank order by macro-area, which do not concern overall unmet medical needs but only the specific stated reasons. The dualism between the North and the South of the country persists. The residual variability across regions is likely to be explained by some organizational characteristics of the regional healthcare services  that are not adequately captured by the determinants used in this analysis.From a public policy perspective, these findings highlight the relative importance of system-related reasons , compared to personal motivations. To be removed, system-related reasons require active health policy responses, which should be multidimensional and differentiated so as to account for the fact that barriers to health care are unlikely to be uniform across groups of people and geographical areas. In this respect, decentralization of health care responsibilities may help to better target resources to population needs and to ensure more effective policy interventions.As for the specific case of Italy, the absolute predominance of cost-related unmet health needs in the South claims for limiting out of pockets payments by patients. This can be done by either reducing co-payments and providing more extensive exemptions or enhancing the quality of public health services, so as to discourage individuals from choosing private services. It is worth noting, that health policies in Italy are, at the moment, following the opposite way: regions with large health care deficits, mostly in the South, have the statutory mandate to increase patient co-payments in order to curb expenditures. There is also evidence  that in There are a number of limitations of this paper. First, as information on unmet health needs is self-reported, some concern could stem from the possibility of unreliable recall. On the contrary, given the specific study purpose, recognition errors due to non-clinically validated data are not a problem. Second, EU-SILC does not enable to distinguish between different experiences of self-perceived unmet health care needs. Specifically, it is not possible to discern situations in which people do not receive health care at all from situations in which they do not receive it in the way they want (e.g. in a timely manner). This fact limits the interpretation of the data, particularly in relation to specific policy options that might be considered to reduce the occurrence of unmet needs. Third, as already mentioned, unperceived unmet needs are completely neglected by the survey. Last but not least, the EU-SILC design is cross-sectional, and, thus, data on outcomes and determinants are collected simultaneously. Because of this, associations observed between variables cannot be inferred to be causal. In particular, the direction of causality can be confounded. This could be the case for the relationship between unmet health needs and the health status variables, which could suffer from reverse causality: unmet needs could exacerbate health conditions and so self-reported health status. In this regard, future research should focus on panel data based on different waves of EU-SILC to better disentangle the role played by each determinant in explaining unmet health needs.1 A part from dental care for which a similarly worded question is addressed in the EU-SILC, the way in which the present question is phrased in Italian could potentially omit certain kinds of health needs. Indeed, each European member state is quite free to decide how to word this question, though within the general framework provided by the EUROSTAT in the EU-SILC technical guidance. Compared to other countries that have opted for a more general and inclusive formulation, the Italian question focuses primarily on specialist care, even if the expression “medical treatment” sounds as quite generic and omni-comprehensive in Italian. This choice is probably due to the fact that in Italy access to GPs is open and free and, thus, it is mainly at the stage of access to specialist examinations and treatments that restrictions show up. In any case, this potential bias is expected to be a serious problem in case of cross-country comparisons but is indeed a minor issue when assessing inter-country differences.The author declares that she has no competing interests.


A recent review has discussed the economic value of vaccine for developed countries. The situation is quite different in developing countries, and we examine the situation in Brazil. Vaccines are of fundamental importance for the control of infectious diseases, especially among the population that lives in poor sanitary conditions. Also, vaccines can generate herd effects that result in protection even among those who have not been vaccinated, which can be of particular value to poor individuals who are not reached by health services. In appreciation of this importance, various international agencies, including the Pan American Health Organization (PAHO) and UNICEF, undertake large-scale procurement of vaccines for supply to developing countries. This scale of procurement has allowed these agencies to obtain very low prices. In Brazil, the Constitution includes the right to health care, which has led the government to formulate a goal of universal vaccination free of charge, a cost-effective measure against many important infectious diseases. Universal vaccination is a fundamental role of the federal, state, and municipal governments through the current unified public health care system (Sistema Único de Sáude [SUS]).To achieve this goal, in 1985 the Ministry of Health (MH) launched a national immunization program and a plan to achieve self-sufficiency in vaccine production through local institutions. The latter program included support for innovation and technological development. The success of this platform has allowed the MH to purchase vaccines from domestic public vaccine production institutes at prices comparable to those obtained by PAHO and UNICEF. Most of the research institutes in less developed countries (LDCs) are the descendants of the various Pasteur-like institutes founded in the early 1900s. Throughout their lives, these institutions maintained scientific research programs but had limited capability for meeting good manufacturing practices (GMPs) in vaccine production. The implementation of the MH policy of local procurement required substantial investments to upgrade the production capabilities of these institutes.The largest volume vaccine producer in Brazil is the Butantan Institute in São Paulo. The Institute, part of the São Paulo State Office of Health, was founded in 1901 to help in the control of bubonic fever and later became a producer of antivenoms and antitoxins. It maintains a scientific research program funded by grants from federal and state agencies. The administration of vaccine production is carried out by the Butantan Foundation, which is a separate, private, non-profit organization closely affiliated with the Institute (The Board of Directors of Butantan Institute and the Board of Curators of Butantan Foundation are composed of the same persons). Because of its legal structure, the Foundation is free of the usual administrative constraints of government agencies. In 2010, around 53 million doses of vaccine were used in the vaccination program implemented by the MH . This coThe situation in Brazil contrasts with that of other developing countries. In India, private for-profit companies have emerged as the major vaccine producers. In China, the situation is mixed, with a number of government controlled non-profit vaccine production institutes and several emerging private sector producers. The private Indian manufacturers have, in several cases, become major vaccine exporters and sell large quantities to UNICEF. The Chinese manufacturers have largely remained as suppliers for local needs. In both India and China, major developed country for-profit vaccine manufacturers are buying interests in the local companies. There are no private sector for-profit vaccine manufacturers in Brazil.The Butantan Institute has employed four methods to obtain new vaccine technology.Technology transfer from for-profit vaccine producers in developed countriesTechnology transfer from public sector institutions in developed countriesIndependent developmentPartnerships with for-profit vaccine producers in less developed countriesWhile this approach can be successful, it has certain disadvantages. The companies are understandably reluctant to create competitors with knowledge and capabilities in the most up-to-date production methods and most advanced vaccines. Thus, the developing country partner may obtain out-of-date technology for older vaccines. Furthermore, the technology transfer agreements may not result in autonomous production capability, as they may require that the recipient of the technology obtains certain essential materials from the developed country supplier. The agreement may also impose a minimum price at which the vaccine can be sold, preventing the achievement of the most cost-effective programs. The agreement may not provide for the recipient partner to obtain new developments in production technology, imperiling sustained economic feasibility. If the agreement calls for stepwise technology transfer beginning with filling and labeling, there may be no guarantee of moving to the next step, resulting in a requirement to continue importing in bulk. The technology supplier may also demand quantities of vaccine for clinical trials without clear benefit for the developing country recipient or the country itself. Despite all the problems mentioned above, this model of technological transfer allowed a successful association between Butantan Institute and Sanofi-Pasteur for the production of seasonal influenza vaccine. The process started in 1999–2000 and the production of the first vaccine lots occurred in 2011. In the beginning, the vaccine was obtained ready for use and Butantan had to perform the quality control. This stage was followed by the implementation of the formulation and filling technologies, which allowed the purchase of the vaccine in bulk. In parallel, human resources were trained in all steps of the production chain and funds were obtained from federal and state agencies for the construction of a production plant. In 2008, the start up of the plant occurred. This important achievement is not only strategic for Brazil, but also for all of Latin America in the case of a pandemic influenza Necator and Schistosoma parasite worms vaccines. Butantan is also working with the Infectious Diseases Research Institute in Seattle and the University of Washington on a Leishmania vaccine for dogs, which are the main reservoir for this disease in Latin America. The main advantage of this kind of partnership is that both sides will complement efforts to bring the potential vaccines to the market at a reduced time when compared with a development made by each partner alone. Depending on the case, the proof of principle in animal models was previously defined. Therefore, in these cases, the scale up of the bench process and the production under GMP conditions for the pre-clinical and Phase I/II clinical tests are the major challenges faced by the partners. It is important to point out that this kind of association is only feasible if the recipient institution counts with well trained human resources and is an active and qualified manufacturer with a well established market. From the point of view of the university and public research institutes involved, this represents a chance of high profit return and project success.As Butantan has proven itself to be technically competent with qualified personnel and modern facilities, it has sought new vaccine candidates from public health research institutes and universities in developed countries. In these programs, Butantan works in partnership to move from pilot-scale production to confirmation of proof of principle, to preparation of lots for clinical testing, and finally to large-scale production. Butantan is executing two such programs in collaboration with the United States National Institutes of Health for a pentavalent rotavirus vaccine and a tetravalent dengue vaccine. It is also undertaking programs with Children's Hospital Boston, of the Harvard Medical School, for a killed unencapsulated whole cell pneumococcal vaccine and with the Sabin Vaccine Institute and George Washington University for the low), formulated as DTwPlow, can be supplied at the same price as the regular whole cell DTwP vaccine. This vaccine was subjected to the standard potency test of intra-cerebral challenge in mice and was shown to induce levels of protection similar to classical DTwP . Furthermore, clinical evaluations were performed in infants and showed immunogenicity similar to classical DTwP and no significant side effects low may increase the yield to about 200 million doses per year, allowing Butantan to export some quantities. Moreover, the LPS removed in this process can be hydrolyzed to monophosporyl lipid A (MPLA), a non-toxic product that can be used as an adjuvant for vaccines like those against influenza H5N1 and pandemic H1N1. The use of MPLA would allow a 4-fold reduction in antigen per dose, simultaneously increasing production capacity and lowering per-dose cost low vaccine, Butantan can produce kilograms of MPLA with only 10 micrograms needed per dose of influenza vaccine. Butantan has agreed to supply another Brazilian public sector vaccine producer, Fiocruz-Biomanguinhos, with DTwPlow ready for combination with lyophilized Haemophilus influenzae type b (Hib) vaccine. To date, Hib has been resuspended with DTwP by the staff at the health care centers to make the tetravalent vaccine right before use.Since 1984, the Butantan Institute has produced diptheria, tetanus, and whole cell pertussis (DTwP) trivalent vaccine for the full cohort of children born each year in Brazil, which currently totals 3.2 million infants. This DTwP vaccine has been highly efficacious, lowering the incidence of all three diseases substantially between 1990 and 2008 . In contlow and hepatitis B is under clinical trial and could be further formulated as a pentavalent vaccine by the addition of Hib produced by Fiocruz-Biomanguinhos. Regarding the Hib vaccine, its production by Fiocruz-Biomanguinhos is under a technology transfer agreement with GlaxoSmithKline that limits the export of the vaccine only to Mercosur countries . To overcome this limitation, Butantan is independently developing a Hib vaccine. This vaccine is expected to have a lower cost of production because of an innovative conjugation method for the polysaccharide antigen and the carrier protein resulting in higher yield. In addition, the carrier protein is also regularly produced by Butantan, avoiding its acquisition in bulk and resulting in a decrease of the final price. Thus, a pentavalent vaccine formulated with the Butantan Hib vaccine could perhaps be provided to LDCs at a price comparable to that obtained by PAHO and UNICEF. Butantan is particularly interested in multivalent vaccines because they have many advantages, such as inoculation of a single dose of adjuvant and the use of a single disposable syringe for many vaccines. In Brazil, the cost of vaccine administration is borne by municipalities and is not included by the MH in the cost of immunization. Between 2 and 18 months of age, each Brazilian receives seven injections to receive DTP, hepatitis B, and Hib vaccines . The combination of PspA with DTwPlow has been shown to improve protection against challenge with several pneumococcal strains in mice Butantan is also developing new pneumococcal vaccines that should be less expensive than existing ones. Pneumococcal-conjugated vaccines containing polysaccharide from seven, ten, or 13 serotypes have prices that are prohibitive for most LDCs. Also, these vaccines may induce serotype replacement, requiring development of new formulations containing additional serotypes low, hepatitis B, Hib, and pneumococcal antigens could substantially reduce the cost to provide protection against a wide range of infections and with fewer injections. A further improvement would be the addition of the Salk inactivated polio vaccine. However, the development of such complex vaccines would require extensive clinical trials.A vaccine combining DTwPIn Brazil, partial protection against tuberculosis is achieved by intradermal delivery of bacille Calmette-Gueri (BCG) at birth . In addiThe scheme in low can be a base for multiple vaccines  since DTwPvaccines  for LDCsThe national immunization program launched in 1985 in Brazil has provided immense public health benefits to the whole country free of charge to individuals. These benefits were achieved through sustained long-term efforts to develop all elements of the program, including product development, production, delivery, and disease surveillance. Vaccination of children, adults over 60 years, and persons with underlying health conditions that make them more susceptible to acquiring preventable infections with the existing vaccines provided by the MH and health care personnel are all covered free of charge through the SUS . This isWhile collaboration between public sector institutions and private sector pharmaceutical companies (from both developed countries and LDCs) can also be successful and complementary for obtaining know-how for vaccine production, it is essential that the resulting products are affordable to ensure cost-effective programs. In addition, any adopted strategy must consider keeping high confidence in vaccines, which is usually greater among populations in LDCs than in industrialized countries