The relationship between hip deformities and osteoarthritis has recently received a lot of attention. In particular, it has been shown that both osteoarthritis and its precursors, such as the hip deformities that lead to femoroacetabular impingement (FAI), are more prevalent in elite athletes compared with the general population. However, the etiology of the above-mentioned types of hip deformity is not currently well understood. Many recent studies have attempted to shed light on the etiology of this disease. In this article, the main clinical, radiological, mechanobiological, and biomechanical findings of relevance to understanding the etiology of hip deformities leading to FAI are reviewed. Based on these findings, a consistent biomechanical theory explaining the development of hip deformities in athletes is then presented. According to the presented theory, the repetitive, impact-like musculoskeletal loads that athletes experience, particularly when they undertake extreme ranges of hip motion, cause the development of hip deformities. According to this theory, these musculoskeletal loads trigger abnormal growth patterns during the years of skeletal development and cause the formation of hip deformities. A number of hypotheses based on the proposed theory are then formulated that could be tested in future studies to ascertain whether the proposed theory could sufficiently describe the development of hip deformities in athletes. Understanding the etiology of osteoarthritis has recently been the center of attention of many researchers. In particular, interest in the link between hip deformities and osteoarthritis that has previously received only limited attention –3, has rFAI is one of the few cases where the etiology of osteoarthritis and the associated risk for inducing cartilage damage havebeen extensively studied and documented –10. FAI Impingement of overgrown bone into the articular surface is one of the latest events in the development of osteoarthritis in FAI patients. A potentially more important question is ‘how does the abnormal anatomy of the femur or acetabulum develop?’ In the general population, there is some evidence that genetics may play a role in the development of hip deformities . Any numThe most important clinical and radiological findings are summarized in this section, with emphasis on the observations that are potentially important for understanding the etiology of the disease. In clinical settings, physical examinations including impingement tests are used to diagnose FAI and determine the range of hip motion . ExampleBefore presenting the radiological findings, it is important to discuss some of the most important concepts used in the radiological analysis of hip deformities. Alpha angle described by Nötzli et al.  is oftenCenter-edge angle (CEA) is used for the diagnosis of pincer-type FAI  and geneSeveral studies have compared the prevalence of hip deformities in the preprofessional, semiprofessional, and elite athletic population with control groups often comprised of healthy individuals or amateur players , 15, 24.p = 0.31) [The prevalence of cam and pincer types of deformity measured using different radiographic parameters  was 70 and 50 %, respectively, among elite male and female soccer players . In a st = 0.31) . The ran = 0.31) . In addi = 0.31) .In a sample of players in the National Football League with a history of hip pain or groin injury, 94 % (116/123) of the hips had radiographic signs of FAI, i.e. elevated alpha angle or decreased head–neck offset ratio . In a siOnly limited information is available in the literature regarding the effects of the type and intensity of physical activity on the development of FAI. In one study, ice hockey players were found to be 4.5-fold more likely to show radiological signs of cam-type FAI, particularly elevated alpha angles, compared with skiers . In a stStudies that investigate the relationship between skeletal development and hip deformities have generally made the following three observations. First, it has been observed that hip deformities start to develop at a very early age, e.g. 10–12 years . Second,Alpha angles exceeding 60° were found for some preprofessional soccer players, as well as some control group members, as early as 12 years of age . In a foA positive correlation between age and alpha angle was observed for ice hockey players but not for the control group . For iceIn a computed tomography (CT)-based study of a population of 225 pediatric and adolescent individuals, the alpha angle was found to increase with age . MoreoveThe presence or absence of symmetry in the development of FAI could give us some clues regarding the potential causes of such deformities in the athletic population. When a population of 22 asymptomatic semiprofessional soccer players was compared with a control group of amateur soccer players, it was found that semiprofessional players have a higher prevalence of elevated alpha angle in their kicking leg compared with the control group . In the In a population of elite soccer players, the prevalence of radiographic cam lesions in men was 68 % (51/75), of which 76 % were bilateral . As for It is important to note that FAI patients undergoing surgery often require bilateral surgery . In geneThe differences between male and female populations in terms of hip deformities have been studied by a number of researchers. In a study of former youth soccer players, the prevalence of cam deformity was found to be higher in men compared with women . MoreoveThe biomechanical and mechanobiological findings regarding the FAI are reviewed in this section. The focus is on the studies and findings that could be used to understand the etiology of FAI.Mechanobiological studies of the etiology of hip deformities in general, and FAI in particular, are rare. In theory, it is possible to use theoretical models of tissue growth and adaptation , 40 and Musculoskeletal loading is directly related to the physical activities undertaken by individuals. In order to study the musculoskeletal loading of athletes, one usually needs to study the movement of their different body segments and the forces exerted to their body during those movements (e.g. the ground reaction force). One could then relate those to internal musculoskeletal forces, including muscle and joint reaction forces, using biomechanical models such as musculoskeletal models , 49 or mThese types of analysis are only scarcely available in the literature. Perhaps the most well-studied case is the case of normal physical activity of symptomatic FAI patients –56; howeThere are nil to very limited biomechanical and functional data regarding the musculoskeletal loads experienced by symptomatic or asymptomatic athletes when performing sport-related physical activities at extremes ranges of hip motion and possibly involving repetitive impact loading. This type of information is the most valuable type of biomechanical data when studying the etiology of sport-related hip deformities.The clinical, radiological, mechanobiological, and biomechanical findings reviewed earlier could be used to propose a theory for the development of hip deformities in athletes. Since the prevalence of cam-type deformity is greater in athletes compared with control groups Sect. , it is rDevelopment of cam-type deformity does not occur after the closure of growth plate or is significantly slowed down: As seen in Sect. There is a positive correlation between training intensity and the radiographic/clinical sings of FAI: We have previously seen Sect.  that theOne of the major challenges in assessing this hypothesis is in developing a unified measure of training intensity. As long as one specific type of sport is considered, it might be acceptable to measure training intensity by the number of training sessions per week or the total number of training hours per week, or similar measures. However, this type of measure will not work when comparing different types of sporting activities. An alternative approach for unifying the different types of sporting activities would be the use of more objective measures such as the magnitude, rate, and frequency of the loads experienced during the training sessions, together with the total training time. However, this will require specific measurement techniques that may prove difficult to implement in professional training settings. Even one step further would be the use of biomechanical models to translate the above-mentioned metrics to the loads experienced by the femur, and combining these with bone tissue growth models that could predict bone shape during skeletal development to better quantify the stimulus for bone growth.The prevalence of cam-type deformity is dependent on the type of sport. Sports that involve extreme ranges of hip motion and high-impact movements have a higher prevalence of FAI markers: This hypothesis has not been thoroughly studied before and needs to be assessed in future studies.In asymmetric sports where one leg is used more intensively, or in more extreme hip motions, the prevalence of FAI markers is higher in the more intensively used leg: A few studies did not find any evidence that the prevalence of FAI markers is higher in the dominant leg of soccer players , 31. On According to the biomechanical theory laid out in the previous section, the high-magnitude, impact-like forces that athletes experience during their years of skeletal maturation could influence the development of the femoral anatomy and contribute to the development of cam-type deformity. In order to assess this biomechanical theory, one needs to develop falsifiable hypotheses that are based on this theory. In this section, we mention some of the hypotheses that have either been not studied before or have been studied only in passing in a few (possibly low-power) studies.The etiology of the hip deformities predisposing individuals to FAI is not currently well understood; however, there has been intensive clinical, radiological, mechanobiological, and biomechanical research during the last few years. The findings of these research projects have provided us with a foundation of facts upon which a theory regarding the etiology of hip deformities in athletes could be built.In this article, the currently available clinical, radiological, mechanobiological, and biomechanical findings relevant for the study of etiology of FAI were reviewed, and a theory consistent with these facts was presented as to how hip deformities develop in athletes. However, the level of evidence available in the literature is not enough to enable us to decisively accept or reject the presented theory. That is why it is of the utmost importance to test the hypotheses presented here Sect. , as wellThe hypotheses presented in the previous section are important for assessment of the validity of the presented theory. However, more could be learned about the potentially developmental nature of cam-type deformity through the study of the relationship between the movements of athletes during sporting activities, the musculoskeletal loads experienced by athletes when undertaking those movements, and the development of cam-type deformity. As previously mentioned, biomechanical techniques, such as motion capture systems, the apparatus for measurement of external forces, and inverse dynamic musculoskeletal models, could be used to understand the type, magnitude, and direction of musculoskeletal loads experienced by athletes when undertaking any given physical movement. On the other hand, the obtained musculoskeletal loads could be used in FE models that incorporate bone growth models to understand whether any given movement could contribute to the development of cam-type deformity by adversely affecting the mechanical bone growth stimulus. If we know which physical movements might contribute to imbalances in the bone growth stimulus, it might be possible to develop compensatory exercises that, although not necessarily needed for the training of players, could restore the balance of the mechanical bone growth stimulus, thereby ensuring that hip deformities do not develop.Robust methodology is, in any case, very important for these endeavors. There are several technical details that are important regarding the methodology used in such investigative studies. In this paper, two specific technical points—one pertaining to clinical and radiological studies and the other pertaining to biomechanical and mechanobiological studies—are highlighted.Regarding the radiological and clinical point, it is important to realize that controversy exists as to whether radiological signs of FAI are indicative of the actual disease , 62. RadAs for the biomechanical and mechanobiological point, an accurate description of the musculoskeletal loading during extreme ranges of motion and impact-intensive physical activities is currently lacking. The proper methodological approach will require the use of motion tracking systems, force plates or pressure-sensitive pads, and patient-specific musculoskeletal models to estimate the detailed loading, including muscle and joint reaction forces when performing physical activities. Due to the lack of such detailed information, mechanobiological studies on the development of hip deformities, for example the study by Roels et al. , will haUltimately, it is important to realize that the decreased range of hip motion in athletes may need to be compensated by increased pelvic motion, thereby subjecting pelvic stabilizers to higher stresses and possibly resulting in damage to the affected soft tissues . FAI in As described by Pun et al. , and fouThe clinical, radiological, mechanobiological, and biomechanical findings seem to hint towards a possible theory for the development of hip deformities in athletes. According to this theory, these types of deformities are caused by abnormal growth during the years of skeletal development that are stimulated by repetitive impact-like musculoskeletal loads experienced by athletes when they perform physical activities involving extreme ranges of hip motion. However, the currently available evidence is not decisive and more high-power studies focused on specific hypotheses predicted by the above-mentioned theory are needed.


The Bougainville Crisis (1988–1997) was the largest armed conflict in the Pacific since WW-II. Despite this, there has been no assessment of the Mental Health and Psychosocial (MHPS) impact of the war. The aim of this paper is to summarize the available data regarding the longer-term MHPS impact of the Bougainville Crisis.A literature review and a sequence of consultations in Bougainville were conducted to identify the MHPS impact of the Bougainville Crisis and the capacity within Bougainville to address these issues.The Bougainville Crisis resulted in violence-related deaths; the displacement of more than half of the population; widespread human rights abuses; far-reaching societal impacts including undermining of the traditional authority of elders and women and damage to cultural values and relationships; property damage; and significant impacts on education and the economy. Conflict-related experiences continue to impact on mental health in the form of trauma-related symptoms, anger, complicated grief, alcohol and substance abuse, domestic violence including sexual assault, excessive alcohol use and a lack of engagement in purposeful activities. Other impacts include an increase in other forms of gender-based violence , population displacement, and adverse trans-generational effects on children exposed to disturbed parental behaviours attributable to conflict exposure. In spite of the evident needs, there is limited capacity within Bougainville to address these pressing MHPS issues.The Bougainville Crisis has had a significant MHPS impact at multiple levels in the society. There is a strong interest within Bougainville to draw on external expertise to build local capacity to address MHPS issues. Preliminary recommendations are made to assist the process of building the capacity in Bougainville to address MHPS needs. The Bougainville Crisis refers to a civil war that occurred between 1988 and 1997 in the North Solomons Province of Papua New Guinea (PNG), now known as the Autonomous Region of Bougainville. The war, which was the largest armed conflict in the Pacific since WW-II  was accoIn October 2009, the first author (DT) was invited by a Bougainville political leader and senior Catholic Nun to engage with local agencies and government on how to address the medium-term MHPS effects of the war. The first author undertook a series of visits and consultations and an extensive literature review on the MHPS impact of the war. The data presented here represents a distillation of first-hand experiences gained during successive visits together with evidence gleaned from existing records and documents. Based on these sources, we review briefly the history of the conflict pertaining to the MHPS impact of the war, and our direct observations from community consultations to reflect on the level of local interest in addressing MHPS issues and the capacity within Bougainville to mount an effective response. We conclude by making preliminary recommendations aimed at assisting in building the capacity in Bougainville to address MHPS needs. In undertaking this task, our explicit intention is to avoid the language of blame in relation to the causes or consequences of the conflict.We provide only a synopsis of the origins and course of the Bougainville Crisis. The complex mix of ethnic, cultural and economic issues that motivated the conflict has been considered elsewhere –7. In NoFailure of PNG police to halt the BRA and growing criticism about its handling of the situation compelled the PNG government to accept a ceasefire in March 1990 . SubsequIn response to a request by Bougainville leaders concerned about the ongoing violence, in September 1990, the PNG Defence Force returned to the administrative centre, Buka Island, to restore and maintain the security and safety of villagers . In JulyWe applied two approaches to assess the longer-term MHPS impact of the Bougainville. First, a review of the literature was conducted to identify the conflict-related events that were likely to have impacted on the longer-term MHPS of the Bougainville population. DT searched key databases including MEDLINE, EBSCO Psychology and Behavioural Sciences Collection, PsycINFO, SocINDEX, PsycARTICLES and internet search engines  using the following terms: Bougainville, Bougainville Crisis, Bougainville war AND psychology, psychiatry, mental health, trauma and impact. While no systematic investigations of the MHPS impact of the war were found, various reports documented events that occurred during the war that, according to past research and knowledge from similarly conflict-affected countries were deemed likely to have had a MHPS impact. Reports referred to herein were compiled by official investigators, academics and others who we judged had applied investigative rigour and impartiality to their assessments. Credibility was judged by the identification of sources, accurate specification of dates and locations, and adequacy of the detail given, for example, in identifying the key groups involved . Reports that were based primarily on opinion or appeared to be advocating for a particular side in the conflict were excluded.Second, during three successive field visits 2009, 2011, 2013), DT made a detailed inquiry into the extent of exposure of the population to conflict-related events, community perceptions regarding current MHPS issues, the level of interest amongst a wide range of stakeholders to address MHPS issues, and the capacity within Bougainville to address these needs. During the 2013 field visit, the Bougainville Mental Health Steering Committee, comprised of local stakeholders, was established to pursue preliminary steps to building capacity in Bougainville in order to address MHPS issues. Subsequently, in 2014, DT, DS and PB were contracted by Counterpart International  with support from USAID to work with the Bougainville Mental Health Steering Committee  to develop a strategic framework to address MHPS issues. Table 1, 2013, Table Table Collectively, the MHPS identified were described as having a broad impact on the social fabric of Bougainville society and, indirectly, on economic recovery. Across the sequence of consultations  there was a broad consensus concerning the priority need to address MHPS issues to reduce the distress experienced by individuals and the burden of associated disturbed behaviours on families, community, health services, the police, the judiciary and educational institutions. The overarching view of our informants was that addressing MHPS issues, particularly trauma related aberrant behaviours had the potential to: assist in healing relationships damaged during and since the conflict; support efforts to maintain and enhance the peace process; and encourage the re-engagement of those affected in purposeful and productive family, community and economic activity. It was recognized that, in addition to the need for MHPS services, traditional reconciliation ceremonies in which perpetrator(s) compensate victims, might play a complementary role in achieving healing for sides of the conflict.While a range of government, non-government  services, agencies and groups are confronted by MHPS issues in their daily work, only a few agencies are specifically focused on assisting persons with these problems. Two such agencies are the Nazareth Centre, which provides refuge for women and other survivors of family violence, youth who have substance abuse issues and treatment for former combatants; and the Leitana Nehan Women’s Development Agency who provide counselling and referral related to gender based violence, trauma-related awareness raising programs and training for community based organizations.In addition to the limited number of trained staff to address MHPS issues across Bougainville, there are minimal resources to attend to people with severe mental disorders including those with psychotic disorders , neuropsychiatric conditions/brain disorders, severe mood disorders and chronic traumatic stress disorders that are typically found in low-income, post-conflict settings –34. Yet This brief overview indicates that while key individuals and agencies have worked valiantly over many years to address MHPS issues, it is evident that the capacity within Bougainville to address these issues is severely limited relative to the demand and this has been noted in a number of reports , 23. TheOn the positive side, important facilitating factors were made evident during the consultations regarding the potential to address MHPS issues, as outlined in Table It is widely accepted within Bougainville that the Crisis left in its wake a range of MHPS issues that require urgent attention. Specific groups have been identified as at high risk of MHPS problems but research in similar situations would suggest a broader community impact. There has also been no assessment of the numbers or needs of those who have severe mental disorders in Bougainville, nor the needs of their families. Although it has been generally assumed that 2 % of any population have a severe mental disorder, findings from a comparable population (Timor-Leste) have found a figure closer to 3 % . In otheThere is a lack of systematic and comprehensive data concerning MHPS needs in Bougainville . The datA sequence of consultations  identified that mental and psychosocial problems are a priority in Bougainville, and that there is broad support amongst politicians, senior public servants, service providers and the general community to build Bougainville’s capacity to address these issues. There appears to be a consensus that addressing MHPS issues would reduce the distress experienced by individuals with MHPS problems and the burden experienced by families and others caring for them. Further, unresolved trauma has been associated with a range of aberrant behaviours  impacting the community at large, as well as a range of specific services  and, more broadly, economic activity , 24. It The following recommendations, developed in close collaboration with the Bougainville Mental Health Steering Committee, have been submitted to the Autonomous Bougainville Government for review . (1) To Although systematic data are lacking, existing information suggests that the majority of people in Bougainville have been significantly affected by the trauma, stress and disruptions resulting from the war. There is an immediate need and a strong interest within Bougainville for assistance to build local capacity to address MHPS issues. This situation warrants assertive and immediate action in relation to the more precise delineation of the mental health status of the Bougainville people and development of comprehensive services to address the multiple needs of the population.


Ancient DNA research is revealing a human history far more complex than that inferred from parsimonious models based on modern DNA. Here, we review some of the key events in the peopling of the world in the light of the findings of work on ancient DNA. The human past on many timescales is of broad intrinsic interest, and genetics contributes to our understanding of it, as do paleontology, archaeology, linguistics and other disciplines. Geneticists have long studied present-day populations to glean information about their past, using models to infer past population events such as migrations or replacements, generally invoking Occam’s razor to favor the simplest model consistent with the data. But this is not the most straightforward approach to understanding such events: the obvious way to study any aspect of human genetic history is to analyze population samples from before, during and after the period of interest, and to simply catalogue the changes. Advances in ancient DNA (aDNA) technology are now beginning to make this more direct approach possible, facilitated by new sequencing technologies that are now capable of generating gigabases of data at moderate cost (Box 1). This abundance of data, combined with an understanding of the damage patterns indicative of authentic aDNA, greatly simplify the recognition and avoidance of the bugbear of the field: contamination.Here, we review some of the key events in the peopling of the world in the light of recent aDNA findings, discussing new evidence for how migration, admixture and selection have shaped human populations.For decades, the theories about the origin of modern humans were summarized in two main competing models: multiregional evolution or recent replacement from Africa , 2. GeneThere are hundreds of research papers discussing the out-of-Africa migration using archaeological data, present-day human genetic data or even genetic data from the human microbiome. Most of this work refines the recent replacement model, including suggesting a time-frame for the expansion  as well Neanderthal ancestry in all present-day non-Africans is estimated to be 1.5–2.1 % . The broHomo species. Future findings will likely show that many of the assumptions reported here were simplified and that, even with aDNA, we still have to invoke Occam’s razor to explain the data: that is, until sufficient human fossils have been sequenced.Admixture with Denisovans also occurred, possibly in South-East Asia , and affaDNA evidence has thus supported the replacement model as an explanation for most human variation, but has transformed and enriched this model in ways not anticipated in the earlier debate: first by discovering Denisovans, whose fossil record currently remains unrecognized, and second by revealing the multiplicity of admixture events, which include at least one that cannot be detected in present-day DNA.Europe was first populated by modern humans around 45,000 ya, but (except for some southern areas) was depopulated during the glacial maximum that occurred 25,000 ya and subsequently repopulated as the climate improved, with farming beginning ~8000 ya during the Neolithic transition (Box 3). Decades of debate have been dedicated to understanding the origin of agriculture in Europe, focusing particularly on whether it spread from its place of origin in the Near East by demic diffusion (movement of farmers) or by acculturation of the indigenous hunter-gatherers (movement of ideas). Geneticists first attempted to answer this question by sampling modern populations from Europe and the Near East and then comparing the genetic diversity of classical protein markers (Box 1) between the two regions.Science magazine featured an image by Cavalli-Sforza and colleagues showing maps of Europe constructed with ten loci using multivariate techniques to reveal clines [In 1978, the cover of l clines , which tl clines , 25 and l clines , with pel clines .Recent aDNA studies reveal, however, that populating Europe has been a much more complex process, and that the Neolithic transition (Box 3) was not even the event that most influenced the present-day genetic landscape.The first aDNA complete genome sequence from Europe came from the Tyrolean Iceman; a 5300-year-old (Late Neolithic or ‘Copper Age’) natural mummy discovered in 1991 in the Ötztal Alps. Surprisingly, the Iceman had more genetic affinity to present-day Sardinians than to the present-day populations inhabiting the region where he probably lived , showingIn summary, aDNA findings have provided conclusive evidence for the movement of farmers at the beginning of the Neolithic transition, but also for the incorporation of the hunter-gatherer gene pool, and therefore support what might be called a ‘leaky demic diffusion’ model. In this respect, the new findings merge the previous ideas. But in demonstrating the large genetic contribution of the Yamnaya during the Bronze Age, they again reveal major events that were not anticipated in the earlier genetic debate.Although it has long been accepted that Native Americans’ ancestors migrated from Asia via Beringia (present-day Alaska) to occupy the Americas, much uncertainty has surrounded both their origin within Asia and the number of migrations. Genetic analyses show that Native Americans are most closely related to northeast Asians, but with different skull morphology. In 1996, the finding of a 8340–9200-year-old male human skeleton along the Columbia River shoreline outside Kennewick, Washington State, USA, heightened the debate on the origin of Native Americans. Initial assessment of the skeleton suggested he was anatomically distinct from modern Native Americans and more closely related to circumpacific groups such as the Ainu and Polynesians. Kennewick man, as the skeleton came to be known, was recently sequenced and found to be genetically closer to modern Native Americans than to any other population worldwide, therefore showing continuity with Native North Americans over at least the past eight millennia, despite the difference in morphology .Insights into the Asian origin of the Native Americans came from a genome sequence of a 24,000-year-old boy found in Mal’ta in south-central Siberia . The MalControversy about the origin of Native Americans was recently sparked once more when analysis of present-day DNA from some Amazonians showed a small proportion of ancestry more closely related to indigenous Australians, Papuans and Andaman Islanders than to any present-day Eurasians or Native Americans, suggesting to the authors that there were two founding populations in the Americas . HoweverThe Paleo-Eskimo cultures that settled in Greenland appear to have also originated from a migration from Siberia, but more recently (~5500 ya) and independently of the early migration that gave rise to the majority of Native Americans. Subsequent migration of the ancestors of the Inuit is evident from the genome sequence of ~4000-year-old Saqqaqman .In this example, the aDNA data support and refine the existing models of the early peopling of the Americas, notably by informing on the different independent migrations and by simplifying the interpretation of the morphological differences between the first Americans and later Native Americans, showing these differences to be part of the same genetic continuum.EPAS1, a transcription factor involved in the response to hypoxia, which most probably helps the Tibetans to live at high altitudes [EPAS1. Other examples include Neanderthal alleles that are enriched in genes affecting keratin filaments, which make up most of the outer layer of human skin and produce hair, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African cold environments [Modern humans have come to inhabit an impressive diversity of ecological niches, many of which required local adaptation for survival. Several genetic signatures of adaptations have been identified by searching for alleles that are at high frequency in specific modern populations relative to other populations. For example, by studying genes that show population-specific allele-frequency differences between Tibetans and Han Chinese, a signal of positive natural selection was detected in ltitudes . Numeroultitudes . This coltitudes ; therefoltitudes . On the ronments . The samAdaptation to non-African environments was also believed to be the cause of human variation in skin color. It was thought that the light skin of Europeans was a Paleolithic adaptation to facilitate vitamin D production in reduced sunlight regions . ConsistThe warming after the last glacial period, followed by the Neolithic transition and the adoption of agriculture, introduced major changes in the lifestyle and diet of human populations. These events are proposed to have triggered new waves of selection that helped humans to adapt to the resulting social and environmental changes. In particular, selection on immune genes was believed to have been increased by the spread of diseases after the Neolithic due to dense settlements and proximity to domesticated animals. aDNA from Mesolithic Europeans shows, however, that adaptive variants associated with pathogen resistance in modern populations were already present in hunter-gatherers before the advent of agriculture . In factaDNA findings are thus now beginning to transform our understanding of recent positive selection in humans, both by introducing new mechanisms such as adaptive introgression, and by showing that our estimates of the timing of selective sweeps derived from models using present-day populations were unreliable, with the consequence that some widely held hypotheses about the selective forces were also unreliable.not parsimonious, and aDNA reveals a much richer history, as in the other examples considered here. In either situation, human evolutionary genetics is moving to a paradigm where we first look for evidence from aDNA and interpret present-day genetic variation in its light.Findings from aDNA research are currently transforming our understanding of human history at an ever-increasing pace. When evolution was parsimonious, aDNA may support the prevailing model, as with the initial peopling of the Americas; but more often, evolution was What are the limits to how far this can go? Very ancient samples more than 100,000 years old and some geographical regions of great interest, such as the Near East and Africa, remain challenging for aDNA research. Both time and poor DNA preservation in hot wet climates may impose insurmountable limits to resolving many questions related to the origin and genetic diversity of our species. Identifying favorable locations within these regions , or releHomo heidelbergensis (‘Sima de los Huesos’) or any sequence data from Homo floresiensis or Homo erectus? Who were the sources of the non-Neanderthal, non-Denisovan archaic admixture already detected? What did Denisovans look like? What were the number, timing and routes of the major expansion(s) of fully modern humans out of Africa? What was the full richness of subsequent human population history and adaptation throughout the world, including episodes that have left no traces in present-day populations? We expect our understanding to be transformed again in these and unforeseen directions, perhaps even before this review is published.In the near future, we look forward to insights into human history ranging from hundreds of thousands of years ago to the past few centuries. Can we obtain nuclear sequences from The distribution of the human blood groups” [Over the past 100 years, the datasets and mathematical methodologies used in population genetics have changed enormously, providing an ever better understanding of human genetic diversity over time and space. In 1954, Arthur Mourant published his ground-breaking book “ groups” , probablThe development of the polymerase chain reaction (PCR) in the 1980s introduced the use of molecular markers to population genetics and allowed, for the first time, the study of evolutionary distances between alleles at a locus. This methodological progress, along with theoretical advances such as identity by descent developed by Gustave Malécot in 1939  and coalThe first widely used molecular markers were variants of the mitochondrial DNA (mtDNA) and the non-recombining region of the Y-chromosome (NRY). mtDNA is inherited maternally and transmitted from a mother to her children, while the NRY is inherited paternally passing down from father to son. These uniparental markers are transmitted from one generation to the next intact (apart from new mutations) and have known mutation rates, allowing straightforward construction of phylogenies and inference of some aspects of population relationships. Uniparental loci are, however, sex-specific and experience strong drift, providing a limited view of the complex human history. For example, Neanderthal mtDNA analysis shows no evidence of admixture with modern humans , althougThe study of genome-wide markers was initiated using microsatellites  but was simplified by the development of single nucleotide polymorphism (SNP) arrays. The effective population size of autosomal variants is expected to be four times that of mtDNA and NRY, making autosomal variants less prone to drift and providing insight further back into human history. Nevertheless, inferences from SNP arrays are limited by ascertainment biases arising from their design, which generally incorporated SNPs that were discovered in a few populations and were inadequate to capture global genetic diversity.The development of next-generation sequencing (NGS) resolved many of the limitations of the previous methodologies by generating gigabases of sequence data from the whole genome, reducing ascertainment biases while increasing the power to detect evolutionary processes. NGS produces large numbers of short sequencing reads. This feature is particularly useful for ancient DNA analysis and has allowed the sequencing of genomes that are tens of thousands of years old, making the direct study of the evolutionary changes over time and space possible. NGS is thus currently revolutionizing the field of population genetics.D and looked at the derived alleles in Neanderthal. The ancestral allele is defined by the Chimpanzee sequence and is labeled A, the derived allele is labeled B. Two possible patterns of SNPs can then be observed and counted: ‘ABBA’ or ‘BABA’. If Human1 and Human2 shared the same history in their relation to Neanderthal, they will not differ in their derived allele frequencies , and D will not differ significantly from zero. Gene flow from Neanderthal to one of the human populations will lead to an increase in the derived alleles that have occurred on the Neanderthal branch in that human population and D will deviate from zero. Green et al. performed the following test: D and found D was always positive from a significant excess of ABBA sites over BABA sites. The test has subsequently become widely used in many different ways.Patterson’s D-statistic is a comparative measure of allele sharing between two populations and an outgroup. It can be used as a formal test for admixture and can provide information about the direction of gene flow. It was first introduced by Green et al.  to show The Neolithic transition or revolution refers to the change in lifestyle of humans from hunting-gathering to agriculture, through domestication of plants and animals, which led to the development of permanent settlements, towns, cities, trade and eventually the rise of civilization. Neolithic transitions occurred independently in several parts of the world; the one that transformed Europe started in the Near East around 10,000 years ago and spread through Europe over the next few millennia. This cultural transition had considerable consequences for human genetic variation by stimulating growth in population size, and triggering multiple expansions and mixtures, as well as adaptation to certain diets and diseases.


A computerised clinical decision support system (CCDSS) is a technology that uses patient-specific data to provide relevant medical knowledge at the point of care. It is considered to be an important quality improvement intervention, and the implementation of CCDSS is growing substantially. However, the significant investments do not consistently result in value for money due to content, context, system and implementation issues. The Guideline Implementation with Decision Support (GUIDES) project aims to improve the impact of CCDSS through optimised implementation based on high-quality evidence-based recommendations. To achieve this, we will develop tools that address the factors that determine successful CCDSS implementation.We will develop the GUIDES tools in four steps, using the methods and results of the Tailored Implementation for Chronic Diseases (TICD) project as a starting point: (1) a review of research evidence and frameworks on the determinants of implementing recommendations using CCDSS; (2) a synthesis of a comprehensive framework for the identified determinants; (3) the development of tools for use of the framework and (4) pilot testing the utility of the tools through the development of a tailored CCDSS intervention in Norway, Belgium and Finland. We selected the conservative management of knee osteoarthritis as a prototype condition for the pilot. During the process, the authors will collaborate with an international expert group to provide input and feedback on the tools.This project will provide guidance and tools on methods of identifying implementation determinants and selecting strategies to implement evidence-based recommendations through CCDSS. We will make the GUIDES tools available to CCDSS developers, implementers, researchers, funders, clinicians, managers, educators, and policymakers internationally. The tools and recommendations will be generic, which makes them scalable to a large spectrum of conditions. Ultimately, the better implementation of CCDSS may lead to better-informed decisions and improved care and patient outcomes for a wide range of conditions.CRD42016033738PROSPERO, The online version of this article (doi:10.1186/s13012-016-0393-7) contains supplementary material, which is available to authorized users. Application of the best research evidence in clinical practice can improve the quality and safety of health care. Successfully translating evidence into practice requires that clinicians are aware of the evidence, agree with it, are confident about delivering the intervention and adhere to it in appropriate situations . FurtherA computerised clinical decision support system (CCDSS) is an information technology to aid clinicians and patients in making healthcare decisions, based on patient-specific data . This isHopeful governments have made substantial investments in healthcare information technology with decision support capabilities , 11. It Despite popular claims, the mere integration of CCDSS in electronic health records is not sufficient to obtain clinical benefit. Some studies estimate that alerts are ignored in 49 to 96 % of the cases . Even thThe Tailored Implementation for Chronic Diseases (TICD) project is developed of methods to tailor knowledge implementation interventions in chronic illness care  consisteCurrent CCDSS implementations are often only superficially tailored to local context and do not always involve the users, neither the patients nor the health professional , 27. AltTherefore, with the Guideline Implementation with Decision Support project (GUIDES), we aim to improve the impact of CCDSS through optimised implementation, based on high-quality and trustworthy decision support content . Here, wA review of research evidence and frameworks on the determinants of implementing recommendations using CCDSSA synthesis of a comprehensive framework for the identified determinantsThe development of tools for use of the framework andPilot testing the utility of the tools through the development of a tailored CCDSS intervention. Finally, the results from the actions described here will inform the design of a large-cluster randomised controlled trial to evaluate the effectiveness of the tailored CCDSS and for identifying optimal implementation strategies in computerised decision support. Figure We will develop the GUIDES tools in four steps, using the methods and results of the TICD project as a starting point:The GUIDES author group includes experts from different countries  with a strong commitment to evidence-based medicine and broad expertise related to the development, implementation and evaluation of CCDSS , 32–36. Two researchers  will use systematic methods to review frameworks, systematic reviews, process evaluations and qualitative evidence pertaining to factors for successful CCDSS implementation. The research questions are: (1) Which factors contribute to the successful implementation of CCDSS; (2) Which frameworks are being used to organise these factors and (3) What is the evidence for the impact of these factors?We focus on the implementation of evidence-based recommendations using CCDSS, but we also include research evidence and frameworks for the implementation of CCDSS in general. We consider the different types of CCDSS with any objective , in any healthcare setting and directed at healthcare professionals and/or patients. From a holistic point of view, we also include papers on the implementation of health information systems in general, if CCDSS is included in the scope. We define success as any desired change in the effectiveness, safety, efficiency, responsiveness, or equity of health services, based upon the outcomes as proposed by the Cochrane Effective Practice and Organisation of Care (EPOC) review group , 39. If We define a framework as any overview or classification of determinants of the successful implementation of CCDSS. Some known examples of general frameworks include the Five Rights model or the ten commandments for effective CCDSS , 29. FraThe screening for systematic reviews will focus on reviews that allow the identification of factors related to successful implementation of CCDSS based on randomised controlled trials. Given that multiple systematic reviews are available, we will select the most recent reviews, those with a broad scope that includes multiple settings, clinical domains or CCDSS functions and those of the best methodological quality. When excluding reviews, we will check that no important information on potential factors is lost.Further, we will identify process evaluations or qualitative studies that followed trials on the effectiveness of CCDSS , 41. SucAfter an initial screening for factorial trials on CCDSS success features, we decided to also conduct a systematic review of randomised trials that compare the impact of different CCDSS determinants. This also includes trials on the effect of adjacent interventions (e.g. academic detailing) to increase the success of CCDSS. A protocol for this systematic review is registered in the PROSPERO database (CRD42016033738).The search strategy is described in the The reviewers will independently assess the selected frameworks according to desirable framework attributes as defined in the TICD project .One reviewer (SVDV) will extract the identified domains and determinants from each selected paper and will use the list of identified determinants and domains to compose a draft framework. To construct this, we will expand on the TICD checklist . When thIf systematic reviews or reviews of qualitative studies provide evidence for the importance of a specific determinant, we will indicate the confidence we have in the evidence as high, moderate or low. Depending on the type of evidence, we will assess this by means of the GRADE or CerQual approach , 45. To Next, we will invite experts within the field and CCDSS developers or implementers to evaluate the preliminary framework. To compile the list of people, we will include the corresponding authors of every relevant paper found in the review phase and combine this with the suggestions by the members of the GUIDES project. It is our goal to include persons across different country settings. Experts will be requested to declare potential conflicts of interests. Every participating expert will receive the preliminary framework and the first part of a structured feedback form with desirable framework attributes  to 5 (very important). Then, for each item, we will calculate the median score, range and percentage of ‘4’ and ‘5’ scores.Based on the new framework, the existing TICD worksheets, discussion among the authors and feedback from key experts, we plan to develop tools to support the tailoring of implementation strategies for recommendations with CCDSS. We will also integrate the findings from the DECIDE project, which develops and evaluates communication strategies to support evidence informed decisions .The tools will contain an overview of CCDSS implementation success factors and best practices, checklists and worksheets regarding the identification of implementation determinants and the matching to implementation interventions. They will also contain practical recommendations on planning and running tailored CCDSS implementation interventions.Each tool will include definitions and explanations on how to use it combined with examples. To ensure usability and usefulness of the tools, we will consider its comprehensiveness, consistency of framing, and usability. The group of experts will receive another invitation for feedback, this time on the tools that have been developed using part 2 of the feedback form  recommendations and for comorbidity-related issues. The experience from these applications will be used to fine-tune the tools.We submitted the protocol for this pilot study as a separate publication in To get multiple perspectives on the use of the GUIDES tools, we also plan to invite CCDSS developers and implementers to a workshop . We willFurther, we will use the GUIDES framework in a systematic review of trials on CCDSS success features (PROSPERO database registration number CRD42016033738). During the data extraction process, pairs of reviewers will independently code the identified trials using the determinants that are listed in the GUIDES framework. We will calculate inter-rater agreement and record the frequency of coding .It is clear that substantial work is necessary to realise the full potential of CCDSS, and guidance for the optimal design and implementation of CCDSS is urgently required . This prHaving patient information available in the electronic health record in a structured/coded format is considered to be important for the implementation of CCDSS . This al


Lupus patients should avoid stress because physical or emotional stress can affect overall physical health. It has been suggested that social support has a positive influence on health status, but there is a lack of information in the literature on the association between the two among lupus patients. The current study investigated the association between social support and self-reported stress and coping status among African American women with lupus using data collected from two linked cross-sectional surveys. No social support differences in groups of high and low stress/coping were revealed; a duplicate study with a larger sample size is required. Stress can be a physical, mental, and/or emotional response to life's changes and demands. Stress can have immediate and chronic effects. The stress response is the set of physical and emotional changes the human body makes in response to a threat or stress . Stress Some researchers have examined both stress and social support and their effects on the mental and physical health of SLE patients, but not their relation to each other. Dobkin and associates  assessedIn addition to life stress and social support, Kozora et al.  examinedWhile the effects of stress and social support on disease activity in lupus patients have been well-documented, there is lack of information in the literature on the association between social support and stress levels among lupus patients. Therefore, the objective of this study was to determine if there is a link between social support and self-reported stress and coping status among African American women with lupus.In brief, this paper reflects the analysis stress/coping and social support data, collected from two linked cross-sectional surveys. Cases analyzed for the current study were participants in the Buffalo Lupus Project and Breakfast with a Buddy Biomarkers of Lupus Study. The Buffalo Lupus Project, a partnership between the Toxic Waste Lupus Coalition and the University at Buffalo, was formed to count the number of people in the Buffalo community who had lupus and other autoimmune diseases and also to uncover any common factors that may elucidate the complex causes of lupus and other autoimmune diseases. At its onset, the Buffalo Lupus Project consisted of a registry and survey. The survey component of the Buffalo Lupus Project focused on the east side of the city of Buffalo, NY, which is predominantly African American. These areas were targeted due to citizens' concern about high rates of autoimmune disease in the area that they believed may be related to the presence of a toxic waste site there. Trained interviewers completed surveys with 66 patients with SLE, 52 of whom were African American women. Survey topics included demographics, diagnosis, health care utilization, residential history, residential history exposure, occupational history, occupational history exposure, smoking history, family health history, and social support.Upon completion of the survey, each participant was invited to participate in the Breakfast with a Buddy Biomarkers of Lupus Study, which was developed to investigate the relationship between inflammation and heart disease in African American women with lupus. Participation in the study included a fasting blood draw, carotid ultrasound, physical measurements, and a short questionnaire assessing traditional cardiovascular risk factors, including stress/coping status.Currently, 317 residents with lupus and other autoimmune diseases have registered with the Buffalo Lupus Project. Out of the 317 current registrants, 194 have reported being diagnosed with SLE, and, of those SLE cases, 92 were eligible to participate in the Buffalo Lupus Project survey due to having ever lived or currently living in zip codes 14211 or 14215. Sixty-six SLE cases completed the survey and all were invited to participate in the biomarkers study; 44 consented, corresponding to a 67 percent response rate. Responses to the social support variables from the Buffalo Lupus Project survey were merged with the Breakfast with a Buddy Biomarkers of Lupus Study database, and those cases who had participated in both projects and responded to both social support and stress questions were selected out for analysis. Forty-three cases had available values for both stress and social support inquiries. After exclusion of those cases with “Do not know/Not applicable” (DK/NA) responses for the dichotomized stress/coping variable, 41 cases were included in analysis.Stress and coping status was measured as self-reported perceived level of stress and ability to cope, using a question, adapted from the American Heart Association (AHA) Coronary Risk Assessment Questionnaire , which aParticipants were asked how many close friends or relatives they saw at least one time per month (none through 5 or more), how many times in a typical week participants talk on the phone , and how often patients get together with friends or relatives . Participants were also asked if they had a support system, if they lived with someone they considered to be a close friend or relative, and if they belonged to any clubs and/or organizations. Confounding variables assessed included age, highest level of education attained, annual household income, smoking status, and race.t-test due to the small sample size by assuming the independence among the high and low stress group.The stress/coping variable was cross-tabulated with each of the six social support variables investigated, using SPSS, and percentages were calculated. Statistical tests were conducted based on the Fisher exact test and Approximately 88 percent of participants were African American and the remaining 12 percent were Caucasian. The mean age of participants was 50.8 years. Less than ten percent of participants completed less than 12 years of school. Approximately 77 percent of participants graduated from high school, and 17 percent attained a college degree or higher. P = 0.02). Additionally, approximately half of participants in the “no/low stress” category reported coworkers to be a part of their support system, while less than a quarter of participants in the “yes/high stress” category (23.1 percent) reported coworkers to be a part of their support system. More than half of participants reported living with someone they considered a close friend or relative, and the majority of participants reported belonging to at least one club or organization (73 percent).Few differences were observed between the two stress categories with respect to the six social support variables investigated . In bothThe current study did not observe social support differences in groups of high and low stress/coping from a predominantly African American sample of middle-aged women with SLE. A key finding indicates that most SLE patients in the current study had social support.There are a variety of reasons where a link between higher levels of social support and lower levels of stress was not observed. There may, in fact, not be a relationship between the two factors. However, statistical tests were not conducted due to small overall sample size and inability to compare such small groups as independent samples when divided into groups of high and low stress. It will require a duplicate study with a larger sample size to determine if findings are reproducible and statistically valid. It is more likely that the homogeneity of the study sample made it impossible to observe existent trends. In addition to very little variability with regard to social support, there was very little variability in the sample with regard to race and education. However, the slight differences in age, race, and/or income (proxy marker of SES) between the two stress categories could have masked the effects of social support. It is also possible that the way social support and stress/coping were assessed was not comprehensive enough and, therefore, did not truly measure what the present study aimed to measure. Other studies of stress and coping in SLE populations used entire scales, such as the Daily Stress Inventory and Daily Hassles Questionnaire , 22–26, It cannot be ignored, however, that social support is one of the most important factors in predicting the physical health and well-being of everyone, ranging from childhood to older adults. The absence of social support shows some disadvantage among the impacted individuals. In most cases, it can predict the deterioration of physical and mental health among the victims. The initial social support given is also a determining factor in successfully overcoming life stress. Studies in the general population have observed that the presence of social support significantly predicts the individual's ability to cope with stress. Knowing that they are valued by others is an important psychological factor in helping them to forget the negative aspects of their lives and think more positively about their environment. Not only does social support help improve a person's well-being, it affects the immune system as well. Thus, it is also a major factor in preventing negative symptoms such as depression and anxiety from developing . While t


Asthma runs in families, and children of asthmatic parents are at increased risk of asthma. Prediction of disease risk is pivotal for the clinician when counselling atopic families. However, this is not always an easy task bearing in mind the vast and ever-increasing knowledge about asthma genetics. The advent of new genotyping technologies has made it possible to sequence in great detail the human genome for asthma-associated variants, and accordingly, recent decades have witnessed an explosion in the number of rare and common variants associated with disease risk. This review presents an overview of methods and advances in asthma genetics in an attempt to help the clinician keep track of the most important knowledge in the field. It has long been known that asthma runs in families and that children of asthmatic parents are at increased risk of asthma. However, asthma is not caused by a single mutation in one gene, and therefore the transmission of the disease through generations does not follow simple Mendelian inheritance typical of classic monogenic diseases, such as Huntington's disease  or sickle-cell disease . Rather, asthma is a polygenic, multifactorial disorder, which means that many factors contribute to its development. These factors are both genetic and environmental; accordingly, the combined action of several genes interacting with one another and with environmental factors causes the condition .Characteristic of multifactorial disorders is that a person's risk of disease depends on the degree of genetic relatedness between that person and the relative with the disease. Furthermore, the risk is usually higher if the relative is severely affected or if the relative was affected at an early age. Unlike single gene disorders, the asthma phenotype is expressed non-linearly and is highly variable. This makes prediction of asthma status for a given genotype, or combination of genotypes, difficult.Looking at the population gives clues about asthma being a heritable trait. First, there are large geographic and racial differences in disease occurrence. For example, the prevalence of asthma in many Western populations is high, up to 20%, whereas populations from the developing world exhibit much smaller prevalence rates, some as low as 1% or even lower . The recWhile it is obvious that the individual risk of asthma is dependent on familial background, the phenotypic expression of asthma may be modified by other genetic and environmental factors. It is deemed that a small number of genes set the individual background risk that is acted upon by another set of modifying genes and also environmental factors. For example, individuals with early-onset asthma more frequently have a family history of asthma than do those with later-onset asthma, suggesting that genes influence the age at onset of the disease . In addiThere are different experimental approaches to establishing a connection between a gene and a disease such as asthma. The two main options are genetic linkage analysis and genetic  association analysis . Linkagemarkers (sequences of nuclear DNA with known location in the genome) positioned along the chromosome. Thus, if a disease is often transmitted to the offspring along with specific markers, it can then be concluded that the gene(s) causing the disease is located close on the chromosome to these markers. In this instance it is important to note that, although multifactorial disorders such as asthma and allergy are regulated by many genetic loci acting in concert, the mode of inheritance can be reduced to Mendelian inheritance at each of these loci. Therefore, the analysis of specific asthma and allergy genes relies on the same principles as the analysis of monogenic traits. Genetic linkage analysis has identified many regions in the genome related to asthma and allergy. Several of the earliest genetic studies of these disorders performed in the 1980s and 1990s used linkage analysis , where numerous genetic variants, often >500,000 SNPs, spanning the entire genome are tested for association with a particular disease. Several GWA studies of asthma and allergy have been conducted and these have identified a number of candidate genes  and among non-related individuals, typically in a case–control population. In the classical sense, the genotype frequencies among a population of diseased individuals, for example, asthmatic individuals are compared with the genotype frequencies in a non-diseased control population . If the gene frequencies differ between the cases and the controls, the alleles are said to be associated with the disease. The classical candidate gene approach association analysis is based on knowledge of a specific gene's role in the regulation of a pathogenic process, for instance, one relating to mucosal cell repair or immune mechanisms. An extension to allelic association analysis, which is ‘assumption-free’, is te genes , 9.Over a hundred different genes have been associated with asthma and the list is still growing. Asthma susceptibility genes fall mainly into three categories relating to 1) functioning of the immune system, 2) mucosal biology and function, and 3) lung function and disease expression , 9. HoweADAM33) was the first positionally cloned asthma susceptibility gene, meaning that its exact position in the genome was identified before knowing about the function of the gene , 6 (HLA-DQ), 9 (IL33), 15 (SMAD3), 17 (ORMDL3/GSDMB), and 22 (IL2RB) associated with asthma. The ORMDL3 gene, in particular, was associatedwith childhood onset, whereas the HLA-DQ gene was related to later-onset asthma. Further, the results showed that 38% of all cases of childhood-onset asthma were attributable to a combination of the identified genes.The largest and most comprehensive study of asthma genetics to date was conducted in 2010 by a consortium of more than a hundred centres worldwide (HLA-DRB1 gene within the class II region of the major histocompatibility complex (MHC) on chromosome 6. However, this locus was not associated with asthma; most of the identified susceptibility loci for asthma were not associated with IgE, suggesting that elevation of serum total IgE has only a minor role in asthma development.The study also found an association between serum total IgE and the Molecular genetic studies of asthma have contributed considerably to the understanding of the pathogenesis and natural history of the disease. Nevertheless, the entire endeavour has translated only sparsely, if at all, into new treatments or modifiable options for asthma. It is now evident that asthma is regulated by many genes, each contributing only marginally to disease risk . Notably1000 Genomes Project was initiated to sequence the genomes of a large number of people and to provide a comprehensive resource of human genetic variation (The human genome contains about 21,000 genes. The recent complete sequencing of the entire human genome is a landmark endeavour with a profound impact on the ways we diagnose, treat, and possibly also prevent a number of diseases in the future. However, the Human Genome Project relied on only a few individuals, and to grasp the more subtle variation between individuals and to create a ‘reference genome’ for human genetic analysis, the ariation . A majorPersonalised medicine is becoming increasingly important in the post-genomic era. The idea behind personalised medicine is to predict, based mostly on genetic information, which patients will experience the best response to treatment. As this field advances, it will be possible to individualise pharmacotherapy based on genetic polymorphisms so that certain drugs are administered only to those patients who are most likely to respond, while harmful effects are avoided in patients who are most likely to experience toxicity and adverse reactions . CandidaEpigenetics is the study of heritable changes of a disease that are not caused by changes in the nucleotide sequence of the genetic code itself. Epigenetic mechanisms are thought to explain genomic adaption to various environmental influences; epigenetic alterations can contribute to the development of disease, as can genetic alterations. Several molecular mechanisms are involved in epigenetic modification, for example, DNA methylation, post-transcriptional histone modification, and modification of non-coding RNAs. These changes are thought to alter the expressivity of genes, leading in turn to differences in disease expression between individuals. However, little is known about epigenetic mechanisms in asthma and allergy, and studies are currently underway to unravel these . The stu


The lung microbiome, which is believed to be stable or at least transient in healthy people, is now considered as a poly-microorganism component contributing to disease pathogenesis. Most research studies on the respiratory microbiome have focused on bacteria and their impact on lung health, but there is evidence that other non-bacterial organisms, comprising the viruses (virome) and fungi (mycobiome), are also likely to play an important role in healthy people as well as in patients. In the last few years, the lung mycobiome  has drawn closer attention. There is growing evidence that the lung mycobiome has a significant impact on clinical outcome of chronic respiratory diseases (CRD) such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis. Thanks to advances in culture independent methods, especially next generation sequencing, a number of fungi not detected by culture methods have been molecularly identified in human lungs. It has been shown that the structure and diversity of the lung mycobiome vary in different populations  which could play a role in CRD. Moreover, the link between lung mycobiome and different biomes of other body sites, especially the gut, has also been unraveled. By interacting with the bacteriome and/or virome, the respiratory mycobiome appears to be a cofactor in inflammation and in the host immune response, and therefore may contribute to the decline of the lung function and the disease progression. In this review, we report the recent limited explorations of the human respiratory mycobiome, and discuss the mycobiome’s connections with other local microbial communities, as well as the relationships with the different biomes of other body sites. These studies suggest several outlooks for this understudied emerging field, which will certainly call for a renewal of our understanding of pulmonary diseases. As part of the continuous host–pathogen–environment interaction from birth to death, fungi have been associated with asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), bronchiectasis at different levels  has its own composition and evolution, which is unique and specific to each individual. It probably evolves according to the pulmonary disease and to the occurrence or not of an acute pulmonary exacerbation . As a coAspergillus species  which colonize the airway during the stable periods. The attack communities are more virulent, usually composed of pathogenic microorganisms which are associated with pulmonary exacerbations such as S. pneumoniae, H. influenza, Rhinovirus, Adenovirus, etc.). Both attack and climax communities can coexist in CF patients’ lungs and together contribute to the lung function decline. In this model, the climax community seems to be able to avoid the patients’ immune responses and/or is more resistant to broad-spectrum antibiotic therapy. In contrast, the attack communities are expected to be more susceptible to antibiotics.Up to now, lung mycobiome exhibited significant composition differences between patients with CRD and healthy individuals according to the limited studies based on next generation sequencing (NGS) technology . Moreovealbicans . C. albine in CF , even ifne in CF , in agrene in CF . In thisThis model or other mathematical modeling together with metagenomic methods could help predict the effects of antimicrobial treatments on the lung microbiome, leading to a more effective use of antibiotic and/or antifungal drugs with different treatment regimens. On the whole, these findings provide novel approaches to addressing the relationship between microbial communities and pulmonary disease. It could help to assess lung infections by favoring the development of new therapeutic approaches and models. More investigations should be carried on this field to improve our knowledge of the role of the mycobiome in the lung microbiome and in chronic diseases, such as CRD.Despite limited research data, the concept of a relationship between the respiratory and gut microbiomes has recently been considered . The humC. albicans. They also proved the impact of the gastrointestinal microbiome perturbation on immune responses in the lung. Only mice with altered gastrointestinal microbiota developed airway allergic responses to intranasal administration of ovalbumin, associated with significant increases in the levels of eosinophils, mast cells, interleukin (IL)-5 and IL-13, INFγ in the lungs, and IgE in serum. The eosinophilic nature of the inflammatory response was confirmed by lung histological analysis. The allergic response was also induced by intranasally delivered conidia of A. fumigatus using the same model to perturb the gut microbiome either in Balb/c or C57BL/6 mice. These studies demonstrated that the effects of gastrointestinal microbiome disruption were independent of the host genetic background, and that the airway allergic responses following this dysbiosis were independent of the nature of the allergen challenge but require IL-13 production in mouse models  also result in modified microbiomes, suggesting an authentic link between nutrition and the development of a microbial lung community , which may directly influence the respiratory microbiome and host immune response through microaspiration . The mycicipants ], Aspergignments . Like thignments .Altogether, these studies support the concept that the indigenous microbiome and mycobiome of the gastrointestinal tract have a profound influence on the development and maintenance of the respiratory microbiome, as well as lung immunity and inflammation. Further studies targeting intestinal–respiratory microbiome interactions are likely to yield important insights into the dynamics and homeostasis of microbiomes, consequently yielding a better understanding of how intestinal dysbiosis may have notable functional consequences in the pathogenesis of CRD. These findings will represent opportunities for establishing the clinical relevance of early intervention in CRD with altered dietary or frequent antibiotic therapy that may contribute to the development of dysbiosis, or probiotic strategies that might change the colonization of the gut plus lung and thereby improve patients’ outcomes. As this field advances over the next several years, we anticipate that studies using larger cohorts, control groups such as siblings, multicenter designs, and longitudinal sampling will add to our knowledge of the lung microbiome and mycobiome.a priori knowledge of existing microorganisms, and consequently represent the most promising investigational strategy in the context of CRD  as a whole in an integrative research methodology without D Figure . In the D Figure , fungi mGiven the significantly increased rate of allergic diseases such as asthma in the westernized countries, understanding the role of the lung microbiome especially the mycobiome will be of interest in coming decades. In addition, there is evidence that the fungal exposure is associated with asthma and chronic inflammatory pulmonary diseases . Fungi aCandida and Streptococcus , these future studies will be dramatically instrumental in improving our knowledge of the pathogenesis of CRD and in developing innovative therapies.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.