text
string | predicted_class
string | confidence
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|---|---|---|
Ten potential off-target sites were identified by online tool Cas-OFFinder (http://www.rgenome.net/cas-offinder/) to identify potential off-target sites. Sequences surrounding these 10 sites and integrated −28 (A>G) mutation site were PCR amplified and deep sequenced using IlluminaHiseq 2500 PE150 as paired-end 150 reads. The primers for off-target site analysis can be found in Table S3. High-throughput sequencing data was analysed as reported. Briefly, Sample sequencing was done on an IlluminaHiSeq 2000 PE150 as paired-end 150 bp reads. The merged paired-end reads of each library were separated based on barcodes in primers (Table S5) by Python scripts and then submitted to cutadapt (v1.11) for trimming primer sequence. The trimmed reads were aligned to reference sequence by means of BWA with default parameters (v0.7.13). Samtools (v1.3, http://samtools.sourceforge.net) and Picard tools (v2.2.2, http://picard.sourceforge.net) were used to build indices and sort reads. GATK (The Genome Analysis ToolKit, version 3.5) Haplotype Caller and VarScan (v2.4.2, mpileup2snp and mpileup2indel with –min-reads2 10 –min-var-freq 0.01) were used to call variants for all samples and the combined variants of which were then divided into indels and SNVs by SelectVariants. Next, we aligned the reference and repaired sequence to the reads of each barcode by bowtie (version 1.1.2, http://bowtie-bio.sourceforge.net/index.shtmL) with no mismatch. The repair rate was equal to the number of repaired reads divided by the number of reference reads.
|
study
| 100.0 |
BE3 and YEE-BE3 mRNA was transcribed using the mmol/LESSAGEmmol/LACHINE T7 ULTRA kit (Life Technologies) following the manufacturer’s instruction. gRNA-1 transcribed using the MEGAshortscript T7 kit (Life Technologies) following the manufacturer’s instruction. mRNAs and gRNAs were subsequently purified using the MEGAclear kit (Life Technologies) and resuspended in RNase-free water.
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other
| 94.56 |
The in-vitro maturation culture medium consisted of G-IVF medium (Vitrolife Sweden AB, Goteborg, Sweden) supplemented with 10% human serum albumin (HSA) solution (Vitrolife), 25 mmol/L sodium pyruvate (Sigma), 75 IU/L recombinant FSH (Gonal-F; Merck Serono, The Netherlands), and 150 IU/L HCG (Ovidrel; Merck Serono, The Netherlands). Immature oocytes were cultured in a humidified atmosphere of 6% CO2, 5% O2, and 89% N2 at 37°C. The oocyte maturational status was evaluated after 15 h of in-vitro culture. Mature oocytes were identified if they extruded a polar body after 15 h of in-vitro culture and were then used for vitrification. Oocytes remaining immature after 15 h of in-vitro culture were considered incompetent for maturation and were discarded.
|
study
| 100.0 |
Oocytes in vitro maturation were vitrified and warmed by commercial Kitazato vitrification and warming kit according to the manufacturer’s protocol. Vitrification procedures were performed at room temperature (25–27°C). The oocytes in vitro maturation were transferred from the culture medium into the ES medium (KitazatoBioPharma Co, JP) for 15 min and then VS for 90 s. The oocytes were aspirated and placed on the tip of the Cryotop (KitazatoBioPharma Co, JP) and the Cryotop sheet were plunged into liquid nitrogen immediately. Warming procedures were performed by placing the Cryotop in a warming solution (TS, 1 mol/L sucrose) for 50–60 s at 37°C and moving into a dilution solution (DS, 0.5 mol/L sucrose) for 3 min at room temperature. The oocytes were transferred onto the bottom of WS1 dish with small amount of DS and kept for 5 min in WS1 solution and were then transferred onto the surface of WS2 dish with minimum amount of WS1, then kept for 5 min in WS2 on a plate warmer (37°C).
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study
| 99.94 |
Thawed oocytes were placed into separate 10 µL manipulation droplets of G-MOPS with 5% HSA and covered with tissue culture oil. After the first polar body of the oocytes reached 12 o’clock, partial zonapellucida dissection (PZD) was performed before enucleation (Ding et al., 2015). Then, they were placed into separate 10 µL manipulation droplets of G-MOPS medium (containing 7.5 µg/mL cytochalasin B, 5% HSA) in a glass-bottom dish at 37°C for 10 min. The spindle was aspirated into the pipette with a minimal amount of cytoplasm and surrounding plasma membrane using Spindle View (Cri Inc.). Enucleated oocytes were rinsed with G-MOPS medium containing 5% HSA and incubated in G-IVF medium with 10% HSA at 37°C in 6% CO2, 5% O2, and 89% N2 for 60 min before fusion. PB1 was aspirated out of ZP by the pipette before enucleated oocyte fused with donor cells. Donor cells were resuspended in a drop containing HVJ-E extract (Cosmo Bio, USA) and were inserted into the perivitelline space of the enucleated oocytes. The reconstructed oocytes were kept in the manipulation medium until cell fusion was confirmed, and then the reconstructed oocytes were transferred into G-IVF medium (10% HSA) and incubated for 1 h before activation.
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study
| 100.0 |
The reconstructed oocytes were parthenogenetically activated by incubation in 7.5 mol/L ionomycin (I3909, Sigma, St Louis, MO, USA) for 10 min followed by incubation in 2 mmol/L 6-dimethylamino purine (6-DMAP; d2629, Sigma, St Louis, MO, USA) for 4 h. Activated oocytes with 1 PN were injected G1 gRNA, Cas9 mRNA, and the ssDNAoligo into the cytoplasm 5–6 h after activation. The survived reconstructed embryos were cultured in microdrops of G-1 medium (Vitrolife, VitrolifeSweeden AB Göteborg, Sweeden) at 37°C in a humidified atmosphere of 6% CO2, 5% O2, and 89% N2 for 42 h. Blastomere of reconstructed embryos were individually aspirated out of ZP by the pipette.
|
study
| 100.0 |
Single embryo PCR amplification was performed as described before (Zhang et al., 2016). Briefly, each embryo was transferred into a PCR tube containing 1 μL lysis buffer, and then incubated at 65°C for 3 h followed by 95°C for 10 min. The lysis product was then amplified using primers listed in Table S6.
|
study
| 95.0 |
Whole genome amplification of the embryos was performed using the PEPLI-g Midi Kit (Qiagen). Briefly, single cell or single blastomere was transferred into PCR tubes containing reconstituted buffer D2 (7 μL), and then incubated at 65°C for 10 min, before the addition of stop solution (3.5 μL) and MDA master mix (40 μL) and incubation at 30°C for 16 h. The DNA preparation was diluted with ddH2O (3:100), and 1 μL of the diluted DNA was used for PCR analysis.
|
study
| 99.06 |
Below is the link to the electronic supplementary material. Supplementary material 1 (PDF 349 kb) Supplementary material 2 (XLSX 11 kb) Supplementary material 3 (XLSX 10 kb) Supplementary material 4 (XLSX 10 kb) Supplementary material 5 (XLSX 10 kb) Supplementary material 6 (XLSX 91 kb) Supplementary material 7 (XLSX 10 kb)
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other
| 99.94 |
A characteristic cultural feature of the Sami, the indigenous people living in Fennoscandia , is its form of singing, the yoik . Yoik has particular vocal characteristics, an ancient history, and is still a living tradition within the Sami culture. What makes yoik distinct at least in some Sami-dominated areas is that it is practiced in many situations as part of everyday life. Since everything can be expressed as a yoik, people may accompany their daily activities with it. Yoik as traditional singing is thus a part of everyday life.
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other
| 99.94 |
The survival of yoik through the centuries despite acculturation and assimilation pressures is in itself a remarkable phenomenon. Therefore we hypothesise that there may be an apparent benefit of yoik and yoik practice within the Sami culture that has protected this cultural marker from extinction. Compared to other indigenous people in the Arctic, Sami public health shows few significant differences to the majority population. Therefore, we assumed that yoik may have had and possibly still has a role as a health promoting and/or resilience factor within the Sami culture.
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other
| 99.9 |
Music, as a particular human entity, has been used throughout times mostly in everyday life to express or alter moods, feelings and emotions . Singing as such can be seen as a fundamental form of self-expression and self-regulation, containing both individual as well as social aspects . Traditionally peoples all over the world sing or have songs accompanying different activities, moods, life events and occasions .
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other
| 99.94 |
Music therapy (MT), as the clinically applied form of music, embraces a wide range of methods including different forms of singing . During the last decade MT has build up an evidence base revealing promising indications of music’s curative potential in neurological as well as psychological disorders [6–11]. Recently the role of music in a wider health perspective of health promotion, that is music as a salutogenic agent, has been widely acknowledged. This development resulted in a new scholarly discipline called “Music and Health” (MH). In addition to traditional music therapy issues, MH focuses specifically on how music may be used to increase wellbeing and quality of life [12–14].
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review
| 99.9 |
A systematic literature search in medical or musical databases on “Yoik/Joik/jojk/sami singing and health” in 2015 and 2016 revealed no results. This does not mean that the significance of yoik as a potential health promoting factor has been unnoticed in academic writing, but in most health related research reports this hypothesis has been discussed within a broader context of culturally important activities or contents of life [15–18]. To our knowledge, there is only one qualitative pilot study directly targeting the question, whether actively practicing or passively listening to yoik can have health-promoting effects and could thus be a cultural resilience factor within the Sami culture. Due to the distinct features of yoik, which can and is often practiced without the use of words, directly expressing feelings and describing its subject with musical means, we hypothesise that a potential mechanism of action maybe through emotion regulation and the feeling of belonging. The aim of this paper is to review the accessible literature in order to build up a body of evidence supporting this theory.
|
review
| 99.9 |
Because the body of knowledge specifically on yoik and health is so limited, we support our theory with evidence of possible benefits of singing to health, literature describing yoik and its possible functions, and evidence on factors that promote and support health. We present studies of Sami public health and a short overview on Sami history to illustrate the complexity of the topic.
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review
| 99.75 |
Our main sources of references are international medical and musical library databases PubMed, ScienceDirect, Web of Science and JStor and Norwegian databases for university libraries. We used search words “Yoik/Joik/jojk/sami singing and health”, “indigenous singing/music and health”, “music and emotions”. Inclusion criteria for yoik was works concerning yoik as music. Nonetheless, the topic turned out to be too heterogeneous and complex and possibly not clinical enough for a systematic or scoping review. Therefore this review is to be understood as theory building Review article striving for a scholarly review of the literature. Moreover, these results are integrated in well established knowledge and theories from stress research, behavioral medicine and health psychology.
|
review
| 99.9 |
Sami is a common name for groups of indigenous people with closely related languages and cultural features, living mainly in northern parts of Norway, Sweden, Finland and Russia. Lifestyles and traditions connected to hunting, fishing, reindeer husbandry and respectively related craftsmanship are often associated with Sami culture . Today less than 10% of individuals with Sami heredity are actively pursuing these traditional practices .
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other
| 99.94 |
This paper focuses on Sami living in Norway, because Norway hosts the greatest part—about 70%—of the total known Sami population of the four countries . Consequently, most of the public health research related to Sami heredity is done among the Sami living in Norway . “The Sami living in Norway” consist of different groups like South Sami, Lule Sami, North Sami and Skolt Sami. This division is based on linguistic and geographical differences and contains of course several other features connected to culture, traditions and places . The Sami were acculturated in the aforementioned countries through an assimilation politics using educational and other public systems. A substantial number Sami children were placed in boarding schools, often miles away from their homes. The purpose of these measure was assimilate these children to the dominating culture by means of education [23–26]. These children, whose native language was Sami, had to learn to speak and learn in Norwegian and refrain from their native language .
|
study
| 96.94 |
The most intense period of acculturation in Norway was from 1851 to 1959. In this period the idea of “Norwegianisation” was a leading ideology based on social-Darwinistic ideas of ethnic Norwegians’ racial superiority, and the importance of nation building with monocultural norms [27–31]. The latter was particularly important in the rebuilding period after WWII . Today the majority of Sami live well integrated life as part of the Norwegian society. This is also the case for those who are self-identified as Sami and choose to participate in Sami culture and politics .
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other
| 99.9 |
Currently the revitalisation of the Sami culture has grown strong and the Sami traditions have been reinvigorated by an increasing awareness and conscious efforts to preserve the Sami culture as a unique and valued part of the Norwegian society. With the foundation of the Sami Parliament of Norway 1989 and the introduction of Sami as the third official language in Norway this process has had visible success. Nonetheless, the revitalising process is by no means concluded and this is particularly true regarding unsolved issues such as the utilisation of natural resources within the traditional Sami geographical regions. Conflicts between mining and reindeer herding, small- and large scale fishery, and other industrial enterprises raise fundamental questions about the rights and ownership of water and land .
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other
| 99.94 |
The history of Sami is to a certain extent similar to the histories of other indigenous people including colonisation, acculturation and marginalisation through forced assimilation and discrimination. The consequences of this history commonly observed in indigenous populations are high rates of suicide, unemployment, substance abuse, low socio-economic status, and somatic diseases like CVD, diabetes, obesity, cancer and early mortality .
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other
| 99.9 |
Sami public health has been subject to systematic long-term investigation for example in the SAMINOR-programme conducted in Norway in 2003–2004 and 2012–2014. This programme covered physical, psychological and health service issues of Sami living in different areas in Norway . The SAMINOR-programme was preceded by the Finnmark study conducted in 1974–2000 which included the whole population of Finnmark—the Sami, Norwegians, Kven, and any others who live in the area . Before these studies only some isolated reports from physicians working in North-Sami areas are available, reporting issues like tuberculosis, echinococcus and high rates of infant mortality [36–38].
|
study
| 99.75 |
Compared to other indigenous people in the arctic circumpolar area, evidence based on data from SAMINOR shows that the Sami living in Norway do not reveal significant differences in most of their public health markers and self-reported health compared to the majority population . However, the Sami do differ from the majority population in that Sami women have higher adult obesity rates in Sami majority areas, and the prevalence of diabetes is higher among Sami in Southern regions where they are a minority . Considerable differences are reported in self-reported cardiovascular diseases between Sami and non-Sami in northern municipalities .
|
study
| 99.9 |
Some studies suggest that the similarity in the frequency of lifestyle-related health challenges in Sami and majority population might be a result of assimilation and acculturation, because transition into the culture’s lifestyles may be followed by an increase in the prevalence of related diseases like CVD, diabetes, obesity and cancer . Eliassen and colleagues discuss that these diseases may also be understood as caused by chronic stress related to assimilation politics. According to Hansen , chronic stress due to ethnic discrimination in areas where Sami are a minority could be a source of a wide range of chronic diseases. Moreover, Samis are to a higher degree than the majority population disposed to violence, ethnic discrimination and bullying . Thus, it is unclear, whether the similarities between the Sami and the majority population are a consequence of similar lifestyle, leading to a similar prevalence of lifestyle related diseases, or the consequences of acculturation pressure, which in consequence leads to a similar disease rate, despite that fact that the Sami culture may include inherent resilience factors with regard to public health.
|
review
| 99.6 |
Nonetheless, there are also caveats regarding the interpretation of Sami health studies: i) The investigation of Sami public health maybe hampered due to low participation rate in some communities , ii) public health surveys might not reach all individuals who might be defined as Sami descendants, because a person has to self-identify as Sami. In particular the North-South migration wave as a result of the burned earth politics of the retreating German troops in World War II known as the “burning of Finnmark”, has scattered people of Sami heritage over the whole of Norway. Many of those who came as refugees to the south decided to not identify themselves as Sami [21,28–30,45–49]. As a consequence, persons of Sami descend are possibly living everywhere in Norway even though they are not aware of it.
|
study
| 91.94 |
Yoik, the singing tradition of Sami, is considered to be ancient with roots presumably in prehistoric times . It is unique to the Sami culture and particular among European singing traditions . This singing tradition is characterised by a special vocal technology that utilises nearly the whole range of the human natural vocal potential and was originally without instrumental accompaniment. Use of words could vary from one region to another, from nearly none in North Sami language area to long epic descriptions in East Sami in Kola Peninsula. The melodies with regular rhythmic and melodic patterns could often be freely played with and improvised on . Additionally, yoik could also be applied to story-telling .
|
other
| 99.9 |
The most commonly referred form of yoik is a direct, vocal musical expression of anything at the yoiker’s perception at the given moment, therefore emotions, landscapes, animals, birds and other people are yoiked . Yoik often accompanies daily living and moods continuously similar to a “sonic painting” of the yoiker’s mind. Or as Buljo writes: “The Sami yoik everything that belongs to human life”. According to yoikers you do not yoik about something, you yoik the thing itself . Therefore yoik can be seen as a kind of “act of creation” as well as self-expression. It can be a way of recalling something or someone or of giving a musical name to something or someone. When missing a person or a place, yoiking the yoik belonging to the missed object or person gives the yoiker the feeling of it . Therefore, unlike tone-painting, yoikers regard yoiking as a direct communication with the innermost being of the object/subject being yoiked .
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other
| 99.9 |
Historically yoik was also used as part of shamanistic healing rituals and was a means of achieving an altered state of consciousness . It was most likely therefore that yoik along with other pre-christian cultural elements and customs was banned as “sorcery” during the early 17th century. The Christian missionaries associated yoik with pre-christian heathen ceremonies and condemned them as “serving the Devil” . Death penalty as punishment for yoiking ended first at the beginning of the 18th century. However, “sorcery” and yoik as part of it was still prosecuted .
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other
| 99.94 |
Originally yoik was practiced in different forms all over the Sami-inhabited area . However, during the assimilation process of the Sami culture yoik as well as many other traditional cultural features of the Sami were fundamentally weakened and had seemingly disappeared in some regions . Moreover the societal and cultural development of what we call “modernity”, that is transition from rural to industrial-technological culture , has likely changed the extent to which yoik is used .
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other
| 99.94 |
However, yoik is going through a fundamental revival as a musical expression. It is taught in kindergartens, schools, high schools and universities, weekend workshops and, not least, festivals . Not only that yoik has survived a history of assimilation pressure as an element of vocal expression and communication in everyday life for many Sami, it has evolved to new forms and in fusion with different musical styles . Alongside the current revival of the Sami culture, especially the younger generation finds yoik anew as a marker of identity and belonging.
|
other
| 99.94 |
Singing is for humans worldwide a way to celebrate life and death, to sooth sorrow and pain, to agitate to work as well as to war, to describe feelings and to tell stories. Singing has its place in spiritual and religious contexts in prayers, hymns and praise of the objects of beliefs. Singing traditions of many nations reveal that singing has had a natural function as a description and expression of the ongoing activity, situation or mood of the singing person.
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other
| 99.94 |
Singing as practiced in Western cultures has received increasing scientific interest during the last decades. Several studies indicate a connection between singing as a means of self-expression, regulation of emotions, and health and well-being [57–59]. Moreover, the availability of psychobiological methodology over the last decades such as the ambulatory assessment of humoral stress markers or functional imaging have confirmed that the experienced stress releasing effects of music have indeed a psychophysiological bases . As Hou in his review elucidates, music-evoked emotions can modulate activities in both cortical and subcortical systems, and across cortical-subcortical networks . Exactly these networks, which extend from the anterior cingulate gyrus to the amygdala are integral and essential to the generation and regulation of emotions. It is particularly interesting that these networks exhibit disturbed functioning in mental and emotional psychiatric disorders.
|
review
| 99.9 |
Nonetheless, the potentially beneficial effects of indigenous singing traditions have to our knowledge predominantly been investigated as an integral part of healing rituals and here in particular within Native American contexts . Vocal practices are understood as a natural and self-evident part of these of traditional healing methods and enhance the efficiency [62–64].
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other
| 99.9 |
In a recent qualitative pilot study on the topic “Yoik and health” conducted in 2015, Hämäläinen and colleagues hypothesise that yoik must be considered an important marker of social and cultural belonging for many Sami people and, moreover, that it may contribute to emotion management . The authors argue that yoik presents a means for a direct and non-cognitive expression of emotions . It is thus different from talking about or discussing feelings, and is in this way rather similar to art related expressions of emotions such as for example painting. An important distinction to other arts is that yoik in some Sami population groups is an inherent part of everyday life, practiced continuously, accessible to everybody, and introduced during the first day of life. It might be interesting in this context, that the singing traditions of for example Inuit of Greenland and Native Americans have many functional similarities with those of the Sami [64–67].
|
study
| 93.9 |
In summary, the fact that singing can promote emotion regulation and stress release and can thus contribute to mental health and possibly beyond that to general health issues is reasonably well documented. Indigenous forms of singing have rarely been investigated with regard to their general health promoting effects, even though their impact within healing rituals is well documented. Preliminary results suggest that the way yoik is practiced where it is still practiced in the traditional way, namely as an integral part of everyday life, makes this form of singing a potential means of emotion regulation and stress relief for individuals who practice it.
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other
| 99.6 |
Both positive and negative emotions correspond to physiological changes. This connection is mostly known through stress and the fight-flight response, however, all emotions including positive ones, have a physiological component to them . According to Antonovsky any emotion whether positive or negative, maintained over time, represents a load to human organism if not acknowledged and handled somehow, such as by adequate expression. Therefore, emotion regulation is necessary for human homeostasis, that is physiological balance and feeling of wellbeing, and an important component in human self-regulation competence .
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other
| 99.75 |
Antonovsky introduced the term “salutogenesis” as a covering concept for factors supporting the maintainance and/or restitution of health. In a salutogenetic perspective, the questions of what causes disease (pathogenesis) is of lesser importance than the question of what maintains health (salutogenesis) . As early as in the 1970s James P. Henry postulated a direct connection between coronary heart disease and chronic stress [71–73]. Henry’s original hypotheses have been modified considerably e.g. to the framework of the allostatic load model which describes the health impact of stress and stressful/traumatic events over the life span [74–76]. However, the fundamental assumption that chronic stress has the potential to lead to chronic disease, or at least has a negative impact on the course of chronic disease, is generally accepted. The role of trauma and especially collective trauma has received wide interest, in particular in connection with the allostatic load model. This model predicts that it is the accumulation of stressful events that may lead to a higher vulnerability for disease, such as Alzheimers disease in old age .
|
review
| 99.9 |
Significant connections have been found between disadvantageous historical factors like discrimination and assimilation pressure and unfavourable public health factors such as high rates of suicide, unemployment, substance abuse, low socio-economic status, and somatic diseases like CVD, diabetes, obesity, cancer and early mortality in indigenous populations . However, compared to other indigenous populations, these public health marker rates are better in the total population of the Sami living in Norway. Where Sami differ to the worse from the majority population in Norway is in their disposition to discrimination, bullying and violence . Nonetheless, social support within a group, in particular a cultural group, constitutes a significant socio-cultural resilience factor, as has been established for example Holocaust survivors. Social support can provide a strong protective factor against the long-term consequences of trauma . Insofar is the hypothesis that belonging to a specific cultural subgroup may have served as e protective factor evident.
|
study
| 99.94 |
With regard to the potential role of yoik as a cultural resilience factor Bals and colleagues report participation in traditional and cultural activities being a significant protective factor for Sami youth mental health . Moreover, in a study of cultural resilience factors among Sami adolescents living in a Sami community, personal yoik was established as being such a factor . Hanssen has presented some interesting findings suggesting a possible significance of yoik as a valuable cultural symbol in intercultural health care communication with elderly Sami patients in nursing homes . Moreover, Hämäläinen et al. conclude that yoik serves as a cultural resilience factor by being an important marker of social and cultural belonging and an instrument for emotion management on an individual bases .
|
study
| 69.8 |
In summary, in the light of the context of salutogenesis, yoik may support individual health through emotion regulation and stress relief on the basis of the person. Beyond that, the fact that yoik represents a fundamental marker of socio-cultural belonging makes this particular form of indigenous singing likely an element of cultural resilience within a population based perspective.
|
other
| 99.9 |
Yoik serves as a means of emotion regulation and stress relief on the level of the individual. To actively yoik and to listen to yoik evokes positive emotions and feelings of belonging. These have been established as an important factor promoting salutogenesis.
|
other
| 99.94 |
Yoik is a significant cultural marker who has survived throughout centuries, even though it was heavily prosecuted. Cultural markers serve as symbols of identity and belonging. Such symbols in a particular a cultural group, can constitute powerful socio-cultural resilience factors.
|
other
| 99.94 |
The role of positive emotions, optimism and belonging/social support as health protective factors has long been established. Even though many of these results are derived from severely traumatised groups, such as holocaust survivors, the accumulated knowledge has nonetheless general and fundamental significance for our understanding of resilience [5–7]. The role of positive emotions such as love and the social bond for human and animal well-being has meanwhile been accepted even in neuroscience . What is less known is the acknowledgement of music as a related human expression. Jaak Panksepp, the pioneer of affective neuroscience describes in his hallmark publication, Affective Neuroscience—The foundation of human and animal emotions, the role of music as such: “That audiovocal experience speaks to us of our humaneness and our profound relatedness to other people and the rest of nature” . It is striking how much this understanding of music resembles the meaning of yoik expressed by many yoikers. What could confirm the neuroscientist’s perspective better than the statement of a female yoiker Biret Risten Sara from Northern Norway: “Where words end and become insufficient to express the depth of the experience, that is where yoik begins” .
|
review
| 99.9 |
Myopia is a common visual disorder with increasing prevalence among developed countries of the world. Current evidence suggests that myopia affects a large portion of the world population, reaching over 90% in Asian countries, and typically develops in children of 6 to 8 years of age. Over the past half-century, rapid progress of myopia has been reported. Treatment of myopia at an early stage is of paramount importance, as shortsightedness poses a significant risk for several ocular disorders which could result in blindness. These conditions include retinal detachment, glaucoma, cataract, and macular degeneration .
|
review
| 99.9 |
A number of optical and pharmacological modalities have been widely investigated for restriction of myopia progression [2, 3]. Clinical trials on spectacles, rigid gas permeable contact lenses, progressive addition lenses, and soft contact lenses have revealed little or no long-term efficacy of these interventions in myopia control [4, 5]. Both tropicamide combined with bifocals and timolol have also failed to show a significant effect on slowing myopia progression [6, 7]. Two randomized controlled trials on pirenzepine revealed encouraging findings; however, research has not been continued for this agent [8–10]. Contradictory evidence exists regarding the effect of undercorrection on myopia progression. Two randomized controlled trials reported that undercorrection enhances myopia development [11, 12]. Recent evidence shows that undercorrection restricts myopia progression compared to full correction in already myopic children, which is in line with former findings from animal studies . Acupuncture has also been investigated for myopia control, but insufficient evidence exists regarding its appropriateness for clinical use .
|
review
| 99.9 |
Recent studies have reported positive findings for atropine eye drops and orthokeratology in the management of juvenile myopia [15–18]. In addition, bifocal and multifocal soft contact lenses designed with new technology constitute an emerging treatment with promising results . Increased outdoor exposure has also been described to have a protective effect on myopia development .
|
review
| 99.9 |
Currently, there are no generally accepted guidelines on the treatment of myopic progression. Various refractive and pharmaceutical interventions have been investigated, but atropine which appears the most beneficial agent has not been approved by the Food and Drug Administration (FDA). Associated adverse events have prevented efficient interventions from becoming widely adopted for myopia treatment [21, 22]. Myopia causes considerable medical and economic impact on society. The cost of treatment is significant to both individuals and society. Annual expenses for myopia treatment are estimated to be greater than for other ocular pathologies, as well as for non-ocular chronic conditions. The quality of life of individuals is also affected due to functional, cosmetic, and psychological implications [23–25].
|
review
| 99.9 |
Further investigation is warranted, due to the existing increasing prevalence of myopia in the worldwide population . Existing evidence, although at a high level, has failed to convince ophthalmologists to uniformly embrace treatments for myopia progression control. A study design that has recently gained interest is the overview of systematic reviews or umbrella review that attempts to bring together and treat synthetically the evidence from systematic reviews with or without meta-analyses in a given domain [27–29]. Thus, there is no overview in existing literature synthesizing the information provided by systematic reviews and meta-analyses on slowing myopia progression in children, and this is the aim of the present study.
|
review
| 99.9 |
This overview has been registered in the PROSPERO database (CRD42017068204) and has been prepared in consultation with the PRISMA-P statement [30, 31]. PRISMA-P checklist is provided as Additional file 1. Any amendments to the protocol until completion of the overview shall be provided with reasons and shall be available to public view.
|
review
| 99.9 |
A purposive literature search will be conducted in the Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment (HTA) Database via Centre for Reviews and Dissemination (CRD) using the keyword “myopia.” A more comprehensive search strategy will be applied in MEDLINE and EMBASE, using medical subject headings (MeSH) and text words related to spectacles, contact lenses, anti-muscarinic agents, myopia, and children [4, 32]. Database search date is 15 January 2017. For all included studies, reference lists will be also searched. MEDLINE search strategy and keywords are provided in Additional file 2. No language, study type, or date restrictions will be used.
|
review
| 99.6 |
Our overview targets are children and adolescents, equal to or less than 18 years of age (at baseline), diagnosed with myopia defined as spherical equivalent refraction ≤ − 0.25 diopters, with or without astigmatism, and without any ocular comorbidities including strabismus and amblyopia. Animals, adult population, patients not suffering from myopia, or patients with myopia and strabismus/amblyopia will be excluded. Studies related to surgical interventions for myopia correction, e.g., refractive surgery will not be considered.
|
review
| 99.9 |
Our primary outcomes will regard myopia progression and axial elongation as efficacy criteria. Myopia progression will be assessed as mean change in refractive error, measured in diopters, per year. Mean change in axial length, measured in millimeters, per year, will also be evaluated. Outcomes reporting a change in other than a 12-month period will also be accepted and described. Reported adverse events will be regarded as safety criteria. A descriptive approach of side effects will be performed, and odd ratios will be presented, if provided by the authors.
|
other
| 99.4 |
We will consider systematic reviews or meta-analyses of randomized controlled trials (RCTs), pseudo-RCTs, and cohort and case-control studies. Network meta-analyses, if available, will also be reviewed. In order to ensure literature saturation, we aim to consider any recently published RCTs found to not have been included in the meta-analyses. Should recent RCTs be identified, these will also be appraised and their findings will be presented and discussed. No language limitation will be imposed. Only human studies with full text available will be analyzed.
|
review
| 99.9 |
Systematic reviews or meta-analyses of poor quality cohort studies, case series, case reports, or expert opinions will not be considered. Narrative reviews that do not systematically search the literature and do not critically appraise the quality of included studies will be excluded.
|
review
| 99.9 |
Two independent authors will perform all screening steps. Title and abstract screening will be conducted with the Mendeley citation management software. The overview authors will screen the titles and abstracts against the eligibility criteria and obtain full reports for all titles that appear to meet the inclusion criteria, or where there is uncertainty. One team of two independent overview authors will manage data in duplicate from each eligible study, using a data collection form in Microsoft Excel, designed specifically to include all the data required. We will only extract data of the included systematic reviews or meta-analyses and not directly from the primary studies, as this process would be beyond the scope of our overview. In cases of disagreement, consensus will be reached with the help of a third author.
|
review
| 99.9 |
For each included study, information will be extracted on the type of included study (systematic review, systematic review and meta-analysis, meta-analysis, or network meta-analysis); publication date; number of databases sourced and searched; last literature search; type of included primary studies (randomized controlled trials, observational studies, or both); country/countries of origin of studies included in each review; number of primary studies in each review; source of financial support (if any); participants’ characteristics (age range); total sample size (or range of sizes of primary studies); type of treatment (optical or pharmaceutical) and dose when applicable; type of control (optical, pharmaceutical, or placebo) and dose when applicable; follow-up period; outcomes that are relevant to our overview question; results; major conclusions; instrument used to appraise the primary studies and the rating of their quality; metric used and effect size (for meta-analyses); p-value (for meta-analyses); confidence intervals (for meta-analyses); additional analyses (e.g. subgroup analysis, meta-regression, sensitivity analysis, for meta-analyses); and handling of heterogeneity (fixed/random effects model, funnel plot, for meta-analyses).
|
review
| 99.9 |
Two overview authors will independently assess the methodological quality of the included systematic reviews and meta-analyses using the ROBIS tool. A qualitative, domain-based assessment will be performed with ROBIS, evaluating eligibility criteria, identification and selection of primary studies, data collection and study appraisal, and synthesis and findings. A tabular presentation of ROBIS assessment for each included review will be provided and will enable comparisons between studies and detection of the possible presence of bias . We will also provide a table presenting a risk-of-bias assessment of primary studies and relevant tool utilized by each eligible review. If the risk of bias of primary studies has not been evaluated by one or more reviews, we will appraise these studies and present our assessment in a relevant table. The strength of evidence for each outcome of interest across the eligible systematic reviews will be evaluated by two independent authors using the GRADE rating [34–36]. In order to minimize the subjectivity of quality assessment process, a third reviewer will be involved to resolve any discrepancies.
|
review
| 99.9 |
The list of included primary studies will be reviewed in order to identify overlapping studies considered in two or more eligible reviews. We will generate a citation matrix presenting all the included reviews and primary publications. We will estimate the overlap by calculating the corrected covered area (CCA), to assess if specific primary studies are overrepresented. CCA will reflect the degree of actual overlap, as it is not influenced by large reviews. Should high or very high overlap be detected, we will retain the review which will be (1) the most recent, (2) containing a higher amount of information, and (3) the most rigorous in terms of methodology, as assessed by ROBIS tool and GRADE scale. We will examine and record whether the results of overlapping studies are concordant, and if many relevant primary studies would be excluded as a result of the above approach .
|
review
| 99.9 |
Two independent overview authors will also examine possible presence of meta-biases, including publication bias, selective outcome reporting, and dual co-authorship. Handling of heterogeneity for meta-analyses and other potential sources of bias will be described [38–41].
|
review
| 99.9 |
To summarize findings, a descriptive synthesis will be performed. Specifically, we will provide tables that include summaries of study characteristics, quality assessment, and major conclusions. Methodological rigor and quality of evidence of the included studies will be reflected by ROBIS and GRADE assessments. The extent of overlapping primary studies will be displayed in our citation matrix, and the corrected covered area (CCA) will provide an estimate of the actual overlap. Our overview outcomes regarding the efficacy and safety of myopia treatments will be stratified and presented according to the type of intervention. For studies examining the same interventions, we will state whether the reported conclusions are concordant. Should any recent randomized controlled trials be found to not have been included in the meta-analyses, these will also be appraised and their findings will be presented and discussed.
|
review
| 99.9 |
Currently, no consensus has been reached regarding the management of myopic progression and no universal guidelines have been established. This study aims to qualitatively synthesize systematic reviews and meta-analyses in order to identify and appraise high-level research evidence regarding myopia control in children and adolescents. Efficient interventions will be identified and side effects will be reported. Recently published randomized controlled trials will also be presented to provide an insight into the most recent available evidence for retarding myopia progression. The results may guide future research in this area and contribute to guideline development.
|
review
| 99.9 |
Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the most frequent causes of pulmonary hypertension (PH). Following the current understanding, CTEPH results as a complication in 0.1–9.1% of the patients with acute pulmonary embolism (APE) from an obstruction of predominantly proximal pulmonary arteries with organized blood clots1.
|
review
| 99.6 |
Evaluation of data from large registries identified a set of risk factors for CTEPH including ventriculo-atrial shunts, infected pacemaker leads, splenectomy, previous venous thromboembolism, thyroid hormone replacement therapy and a history of malignancy12. Although dysregulation of thrombosis and thrombolysis is observed in a subgroup of CTEPH patients3 this mechanism does not fully explain the pathophysiology. Important classical thromboembolic risk factors are lacking and in about 25% of the CTEPH patients APE occurred asymptomatically1. Hence, the mechanistic view of CTEPH as a consequence of central pulmonary vessel obstruction appears to be too simplistic1.
|
study
| 99.5 |
Pulmonary arterial hypertension (PAH), another main PH group, shares several features indistinguishable from CTEPH: histopathology of peripheral vascular lesions4, acute vasoreactivity testing1, extent of endothelial dysfunction (ED)5 and fibrin resistance to lysis136. However, it is still unknown which exact pathophysiological mechanisms separate these two diseases from each other and in which areas the diseases can be seen as one entity.
|
review
| 99.8 |
Increase of pulmonary vascular resistance in PAH is related to different mechanisms, including vasoconstriction, loss of distal arteries, proliferative and obstructive remodelling of the pulmonary vessel wall, microthrombosis, and inflammation. The latter mechanism gained attention as elevated concentrations of inflammatory markers such as interleukin (IL)-1, IL-6, IL-13, and tumour necrosis factor-alpha were detected in PAH patients plasmas and tissues7. Recently, C-reactive protein (CRP), representing the most established clinical marker of inflammation, was shown to be a prognostic factor in PAH patients8. To which extent inflammation is relevant for CTEPH pathogenesis is uncertain.
|
review
| 99.25 |
The plasmatic glycoprotein fibrinogen is both marker of inflammation and central player in the coagulation cascade9 characterised by its interaction with thrombin leading to conversion of fibrinogen to fibrin by limited proteolysis. Fibrin-stabilising-factor then causes cross-linkage of fibrin-molecules and consequently thrombus formation. Fibrinogen is induced by IL-6 as part of the acute phase reaction10. Interestingly, fibrinogen concentrations have recently been shown to be elevated in a small cohort of PAH patients11 and elevated fibrinogen plasma concentrations are considered as risk factor for coronary heart disease12. However, the diagnostic or predictive potential of fibrinogen has not yet been assessed in PH.
|
study
| 99.94 |
In the present study we aimed to (a) investigate whether fibrinogen plasma concentrations are elevated in patients with PAH and/or CTEPH, (b) characterise possible differences between patients with PAH and CTEPH regarding fibrinogen plasma concentrations and (c) evaluate a potential association of fibrinogen plasma concentrations with established risk factors for disease progression and severity in both groups.
|
study
| 99.94 |
A total of 112 patients were included in this study - 52 (46%) patients with PAH, 49 (44%) with CTEPH and 11 (10%) control individuals with suspected pulmonary hypertension that was eventually ruled out by right heart catheterisation (RHC). PAH patients comprised idiopathic PAH (n = 39), familial PAH (n = 3) and PAH associated with portal hypertension (n = 6), connective tissue disease (n = 2) and congenital heart disease (n = 2).
|
study
| 99.94 |
Baseline demographics, hemodynamic, inflammatory and disease severity parameters of the study population are given in Table 1. Clinical baseline parameters did not differ between PAH and CTEPH subgroups except gender and height. PAH and CTEPH patients had severe disease as reflected by highly elevated mean pulmonary artery pressure (mPAP), mean pulmonary vascular resistance (PVR) and a World Health Organisation function class (WHO FC) of III or IV in the majority of the patients (88% and 85%, respectively). PAH and CTEPH groups did not differ regarding hemodynamic status or functional class. Median follow-up was similar in both groups: 33 months (range 4–111) in the PAH and 34 months (range 1–108) in the CTEPH subgroup.
|
study
| 99.94 |
At time of initial RHC patients with PAH or CTEPH showed significantly elevated fibrinogen plasma concentrations (PAH: 4.1 ± 1.4 g/l, p = 0.0035; CTEPH: 4.3 ± 1.2 g/l, p = 0.0004) compared to non-PH control patients (3.4 ± 0.5 g/l, mean ± standard deviation).
|
study
| 100.0 |
No significant differences in fibrinogen concentrations were detected between PAH and CTEPH (Table 1 and Fig. 1A). Eight CTEPH patients (16%) underwent pulmonary endarterectomy (PEA) following the initial RHC. Fibrinogen concentrations from CTEPH patients undergoing PEA in the later course did not differ from inoperable CTEPH patients (Fig. 1B).
|
study
| 100.0 |
In the control group, fibrinogen plasma concentrations only correlated with age and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) concentrations (Table 2, left columns). In PAH patients, fibrinogen plasma concentrations only correlated with CRP concentrations but not with demographic, haemodynamic or disease severity parameters (Table 2, middle columns).
|
study
| 100.0 |
Intriguingly, in CTEPH patients fibrinogen plasma concentrations were correlated with haemodynamic measures (right atrial pressure, RAP; mPAP, PVR, and cardiac index, CI) and disease severity markers (NT-proBNP, 6-minute walk distance, 6-MWD, arterial partial pressure of CO2, PaCO2) but not with demographic data (age or gender; Table 2, right columns).
|
study
| 100.0 |
In addition, Analysis of Variances (ANOVA) revealed a gradually increasing association between WHO functional class and fibrinogen concentrations in CTEPH (WHO FC II 3.3 ± 0.4, WHO FC III 4.3 ± 0.2; WHO FC IV 5.7 ± 0.5 g/l, p = 0.0172) but not in PAH patients (Fig. 1C+D).
|
study
| 100.0 |
Linearity of fibrinogen plasma concentration with clinical and haemodynamic parameters was tested by regression analysis. In univariate analysis fibrinogen concentrations were significantly associated with RAP, mPAP, PVR, CI, and 6-MWD (Table 3, left columns).
|
study
| 100.0 |
To test independence of fibrinogen plasma concentrations from demographical data and disease severity a multivariate analysis including age, sex, WHO functional class, fibrinogen and the hemodynamic and functional parameters identified in univariate analysis (RAP, mPAP, PVR, CI, and 6-MWD) was performed. Here, fibrinogen was confirmed as an independent marker of haemodynamic impairment as RAP and mPAP were independently associated with fibrinogen concentrations (Table 3, right columns). In addition, PVR and CI showed a non-significant trend to be associated with fibrinogen concentrations.
|
study
| 100.0 |
Clinical significance of this cut-off value was further tested by contingency analysis of haemodynamics, clinical characteristics and fibrinogen plasma concentrations. Fibrinogen plasma concentrations above 3.65 g/l were strongly associated with unfavourable haemodynamic parameters including mPAP (p = 0.001), PVR (p = 0.004), RAP (p = 0.007) and central venous oxygen saturation (SvO2, p = 0.006). Furthermore, a fibrinogen concentration >3.65 g/l was also linked with elevated CRP concentrations (p = 0.023, Table 4).
|
study
| 100.0 |
In the present study we found that fibrinogen plasma concentrations were elevated both in patients with PAH and CTEPH compared to non-PH patients at risk. We could show that in CTEPH patients, but not in PAH patients, fibrinogen plasma concentrations were correlated with markers of disease severity, haemodynamics and CRP concentrations (as a surrogate marker for inflammation). Most importantly, fibrinogen plasma concentrations represent an independent predictor of impaired haemodynamics in CTEPH. Moreover, ROC analysis for detection of at-risk CTEPH patients showed a high specificity with a moderate sensitivity.
|
study
| 100.0 |
Despite numerous studies investigating coagulation parameters, we revealed elevated fibrinogen plasma concentrations in CTEPH patients for the first time. Huber et al. found fibrinogen concentrations to be increased in PAH and “secondary” PH as opposed to healthy controls and patients with PH related to Eisenmenger's reaction13. In contrast, Welsh et al. detected increased fibrinogen concentrations only in patients with associated forms of precapillary PH but not in idiopathic PAH14. Interestingly, fibrinogen concentrations correlated with mPAP in the combined population of their study. In our study, we found elevated fibrinogen concentrations in both PAH and CTEPH patients compared to non-PH controls. However, the independent association with haemodynamic parameters (RAP, mPAP) was only found in CTEPH patients. In contrast to all existing studies, our control group was not recruited from healthy individuals but from patients with suspected PH. Despite diseases with known substantial inflammatory activity within the control cohort – i.e. coronary artery disease and systemic sclerosis –, we were able to reveal significantly different fibrinogen concentrations between the control group and PAH or CTEPH patients (regardless of fibrinogen being considered as an acute phase protein).
|
study
| 99.94 |
Our observations raise the question why fibrinogen concentrations are elevated in PAH and CTEPH: First, fibrinogen may be a marker indicating a pro-coagulant condition. Second, fibrinogen may be elevated in response to inflammatory activity in PAH/CTEPH, which could be initiated by a systemic or localized inflammation within the pulmonary vascular bed. Third, fibrinogen per se may be a central mediator of inflammation leading to vascular remodeling in CTEPH.
|
study
| 100.0 |
The first hypothesis is supported by findings that elevated fibrinogen concentrations were associated with increased thrombus formation and blood viscosity in PH patients15. Also, when obtained from CTEPH patients, fibrinogen is known to be relatively resistant to in vitro proteolysis by plasmin16 and a specific fibrinogen Aα polymorphism increased the risk of developing CTEPH by strengthening the fibrinogen chain cross-linkage17. Fibrinogen's pathological impact on coagulation in CTEPH was further substantiated by a high prevalence of 5 different dysfibrinogenaemias (fibrinogenSan Diego I-V) among patients with CTEPH. All 5 dysfibrinogenaemias seem to confer resistance to fibrinolysis thereby fostering CTEPH development18.
|
study
| 100.0 |
A review of established CTEPH risk factors corroborated a potential role of fibrinogen in coagulation-dependent CTEPH pathogenesis. These risk factors included pacemakers19, splenectomy20, non-0 blood type21, lupus anticoagulant22, thyroid replacement therapy/subacute hypothyroidism23, malignancy24 and age10.
|
review
| 99.9 |
The hypothesis of a pivotal role of inflammation in PH pathogenesis is underlined by various studies investigating circulating inflammatory markers. i.e. IL-1 and IL-6, perivascular infiltrates and tertiary lymphoid tissues in PAH patients7. Intriguingly, inflammation seems to play a role in CTEPH pathogenesis, too, since markers of inflammatory activity (tumour necrosis factor (TNF)-alpha and monocyte chemoattractant protein-1, MCP-1) were found to be elevated in CTEPH and decreased after PEA2526. Interestingly, MCP-1 concentrations were higher in arterial compared with mixed venous blood suggesting increased production or reduced clearance within the pulmonary vasculature27.
|
study
| 88.0 |
Differences in biomarkers of inflammation and coagulation may help to distinguish PAH from CTEPH. Apart from our findings regarding fibrinogen concentrations, differences between PAH and CTEPH were found for IL-6, CRP, soluble CD-40-ligand and fractalkine82527. All these data confirm that both diseases, despite the significant overlap, may have distinct pathophysiology. CRP, for instance, was found to be elevated both in PAH and CTEPH82527, but was only correlated with outcome in PAH and not in CTEPH patients.
|
study
| 99.94 |
However, Wynants and colleagues also report increased proliferative, coagulatory and chemotactic activity of primary pulmonary artery endothelial (PA-EC) and smooth muscle cells (PA-SMC) from CTEPH patients after stimulation with CRP28. In our population we were able to confirm a correlation between CRP and fibrinogen concentrations suggesting a similar cross talk between inflammation and coagulation.
|
study
| 100.0 |
In addition, chronic exposure of PA-EC and PA-SMC to fibrinogen induces altered cytosolic calcium responses, which are likely to confer to vascular remodelling29. Furthermore, fibrinogen directly enhanced vasoconstriction through increased endothelin-1 release from PA-EC30 and indirectly via its degradation products fibrinopeptide A and B31.
|
study
| 100.0 |
Indeed, it has been shown that fibrinogen depletion not only diminished inflammatory responses but also myocardial remodelling in an ischemia-reperfusion model32. These observations support the hypothesis that fibrinogen might not only be a marker of inflammation in the studied processes but seems to contribute to vascular remodelling per se.
|
study
| 100.0 |
Nevertheless, our study reflects “real-life” data from two independent German PH referral centres (with a relatively small sample size). We could detect independent associations between fibrinogen plasma concentrations and impaired haemodynamic parameters in CTEPH patients. It is important to note that in our study PAH and CTEPH patients also did not differ regarding the extent of haemodynamic impairment. Therefore, a bias due to different disease severities was minimized, which was often not the case in previous studies.
|
study
| 100.0 |
A possible reason why we did not detect an association between fibrinogen concentrations and parameters of disease severity in PAH patients might be due to the heterogeneity of the underlying pathologies associated with PAH, e.g. scleroderma or HIV. Due to the small number of patients within each subgroup we were unable to identify a statistical relation of this aspect. In addition, fibrinogen plasma concentrations are influenced by a plethora of lifestyle and demographic factors such as gender, age, body weight, physical activity, smoking or stress10. In order to minimize these influences, we matched our study population with regard to age, sex and body weight. Moreover, anticoagulatory therapy was not administered in a controlled fashion. However, since vitamin K-antagonists do not seem to influence fibrinogen plasma concentrations, we do not believe that this issue provided a relevant bias to our data1033. Actually, heparin (that was used routinely before RHC in our patients) even seems to decrease fibrinogen plasma concentrations34. On the contrary, due to the small sample size and lack of an independent evaluation/follow-up cohort, we cannot rule out an overestimation of fibrinogen's role as a predictor of impaired haemodynamics in CTEPH. Additional limitations of the study include its retrospective nature and a low mortality within our CTEPH population, which made a statistical correlation of fibrinogen to survival impossible. Also, other coagulatory parameters (e.g. D-dimers or prothrombin fragments) that might have helped to distinguish between a thromboembolic and inflammatory nature of increased fibrinogen plasma concentrations were not available for our analysis.
|
study
| 99.94 |
In summary, fibrinogen plasma concentrations are elevated in PAH and CTEPH patients compared to control patients at time of initial RHC. In CTEPH but not in PAH patients increased fibrinogen concentrations predict impaired haemodynamic parameters and clinical severity. This correlation, which is supported by experimental data from other groups in PA-EC and PA-SMC signalling, together with the fact that established risk factors for CTEPH seem to be associated with elevated fibrinogen concentrations, indicate a central role of fibrinogen in the pathophysiology of CTEPH. Therefore, we strongly believe that fibrinogen is a hitherto unrecognized diagnostic and disease severity marker in CTEPH, which warrants further experimental and clinical studies.
|
study
| 99.94 |
At the two participating German centres (University Medical Centre Hamburg-Eppendorf, Hamburg, and Carl Gustav Carus University Hospital, Dresden) the attending physicians retrospectively evaluated all patients presenting to the pulmonary hypertension clinics between January 2001 and January 2010 (Dresden) or November 2011 (Hamburg) for inclusion into this study.
|
study
| 99.94 |
Inclusion criteria were as follows: 1. >18 years of age, 2. Proven pre-capillary pulmonary hypertension as determined by RHC with an mPAP of ≥25 mm Hg in combination with pulmonary artery wedge pressure (PAWP) of ≤15 mm Hg, 3. Clinical classification into WHO groups I or IV following current guidelines35, and 4. Determination of fibrinogen plasma concentrations at time of catheterisation (within 3 days around the procedure). In all patients, lung ventilation and perfusion scintigraphy was used in addition to thoracic computed tomography.
|
study
| 99.75 |
Patients belonging to Dana Point/WHO group II, III or V, patients with documented haematological disorders or significant coagulopathies including liver failure or elevated liver enzymes > 2.5-times upper normal limit were excluded. Anticoagulation was switched from coumadin to low-molecular-weight heparin prior to right heart catheterisation. PEA was offered to all patients with CTEPH who were deemed eligible candidates. During the same time frame a control group was generated from patients referred to the Hamburg centre with suspected PH that was eventually ruled out during the course of clinical workup (n = 11 patients). These cases were selected intentionally as control patients and should not be considered as healthy individuals as they reported symptoms severe enough to justify right heart catheterization in the first place.
|
study
| 99.94 |
All data analysed within this study were obtained during clinical routine, de-identified and retrospectively transferred into an anonymised database before evaluation. No additional testing or procedures were performed for this study. Local law (Hamburgisches Krankenhausgesetz, HmbKHG, §12, 1–3 and §12a, 1–5) regulates the use of patient data in accordance with the Declaration of Helsinki and specifically approves the use of anonymised data for retrospective analyses without individual informed consent thereby superseding Institutional Review Board approval. This study was conducted in full accordance with the principles and requirements of the Declaration of Helsinki and HmbKHG.
|
other
| 99.9 |
Charts of patients were retrieved and data concerning demographics, Dana Point/WHO classification, WHO functional class (FC), 6-MWD, right ventricular systemic pressure (RVSP), CI, mPAP, RAP, PVR, systemic vascular resistance (SVR), SvO2, PaCO2, fibrinogen plasma concentrations, CRP concentrations, NT-proBNP concentrations, observation time and mortality was extracted wherever possible.
|
study
| 99.94 |
At time of visit for RHC, all blood samples except for SvO2 (obtained during RHC) and PaCO2 (arterial or capillary blood gas analysis) were obtained by venipuncture of a peripheral vein during routine clinical and diagnostic workup. All samples were analysed immediately. For fibrinogen assessment, blood was drawn into standardised 3.1% (v/v) trisodium citrate tubes at a final citrate to blood ratio of 1:10 according to manufacturer's instruction (Sarstedt, Nümbrecht, Germany) and processed using a fully automated haemostasis analyser (BCS XP, Siemens Healthcare, Erlangen, Germany) with the Multifibren U reagent kit (Siemens Healthcare, Erlangen, Germany). Reference values for fibrinogen plasma concentrations within this study were 1.8–3.5 g/l.
|
study
| 100.0 |
Statistical analyses were performed using SPSS 17.0 (SPSS Inc.; Chicago, Illinois USA) and GraphPad Prism 5.0 (GraphPad Software Inc.; La Jolla, California USA) from an anonymous database. Normally distributed continuous variables (Kolmogorov–Smirnov test) were expressed as mean ± SD unless otherwise indicated. Differences between continuous variables were analysed using unpaired t-test with Welch's correction. Differences between two nominal variables were analysed using the chi-square test. ANOVA was used to analyse differences between more than two groups. Associations between variables were assessed by Pearson and Spearman correlation coefficients, respectively. Variables, which significantly correlated with plasma fibrinogen concentrations were further analysed in an univariate linear regression model at first. Multivariate linear regression analysis with forced entry selection of the covariates age, sex and WHO FC was constructed afterwards. Two-sided values of p < 0.05 were considered statistically significant.
|
study
| 100.0 |
Specifications TableTableSubject areaNeuroscienceMore specific subject areaComputational NeuroscienceType of dataStatistical regression parameter setHow data was acquiredThis dataset is based on high-resolution T1 3D structural MR imaging data of 1919 subjects acquired at 1.5 and 3 T from four publicly available datasets (NIH, C-MIND, fCONN, and IXI)Data formatAnalyzed dataset in Matlab ® datafile format (*.mat, v7.3)Experimental factorsWhile employing a multivariate adaptive regression splines, demographic (age and gender) as well as technical (field strength and data quality) factors were taken into accountExperimental featuresImages were segmented using the CAT12 toolbox and spatially normalized therein using an affine-only spatial normalization approachData source locationAll source data is available from the contributing studies (NIH, C-MIND, fCONN, and IXI) at their respective websitesData accessibilityThe dataset as well as the algorithms used are freely available at https://irc.cchmc.org/software/cerebromatic.php
|
study
| 90.1 |
Value of the data•Segmentation and spatial normalization of brain MR imaging data routinely makes use of reference, or template brains, which have to be appropriate for the dataset under study•Instead of simply averaging participant's data, template creation can also be achieved using statistical regression approaches, which allow for taking into account key demographic and technical predictors of the dataset•For high-dimensional warping approaches such as the popular DARTEL or SHOOT algorithm, a large population is needed to create high-quality templates, which is not always available especially for “unusual” populations such as infants and older participants•This dataset is the result of analyzing a large population of healthy subjects using a multivariate adaptive regression splines approach, allowing for the customized creation of high-quality sets of brain templates to be used within the DARTEL/SHOOT framework•Such externally-generated but matched templates are particularly useful when only a small and/or “unusual” dataset is available for study
|
study
| 99.9 |
This dataset is the result of analyzing a large population of healthy subjects using a multivariate adaptive regression splines approach, allowing for the customized creation of high-quality sets of brain templates to be used within the DARTEL/SHOOT framework
|
study
| 99.94 |
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