Summary of the features and outcomes of clinical interventional studies in SAH patients.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"79",leadTitle:null,fullTitle:"Multi-Agent Systems - Modeling, Control, Programming, Simulations and Applications",title:"Multi-Agent Systems",subtitle:"Modeling, Control, Programming, Simulations and Applications",reviewType:"peer-reviewed",abstract:"A multi-agent system (MAS) is a system composed of multiple interacting intelligent agents. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"73087",title:"Experiences of Sexual and Reproductive Healthcare Professionals Working with Migrant Women Living with Female Genital Cutting in Western Australia",doi:"10.5772/intechopen.93353",slug:"experiences-of-sexual-and-reproductive-healthcare-professionals-working-with-migrant-women-living-wi",body:'\nFemale genital mutilation/cutting (FGM/C) is practised beyond the borders of countries where it is traditionally reported. Through the influx of asylum seekers and refugees to host countries such as Australia, FGM/C is increasingly creating challenges for healthcare professionals, who may have no or few culturally specific skills to work with its presentation in migrant women [1]. The sexual and reproductive needs of migrant women living with FGM/C are unique, and without culturally specific healthcare frameworks, meeting the healthcare needs of these women may be inhibited by cultural, environmental, and language barriers [2].
\nThe World Health Organisation (WHO) classifies FGM/C into four categories: Type I, Type II, Type III and Type IV. Type III is described as the most severe, whilst Type IV is described as only symbolic and not a ritual [3]. There are two forms of Type I. Type Ia involves the intentional removal of the hood of the clitoris and seldomly occurs on its own [4, 5]. Type Ib results in clitoridectomy—a procedure requiring the removal of the clitoral hood. Type Ib is more common and may also include the partial or complete removal of the clitoris together with that of the prepuce [6]. In Type II (excision), the clitoris and labia minora are partially removed with sharp objects, although some cultures partially cut out the labia majora and may apply ashes or herbs to stop the ensuing bleeding [5, 7]. FGM/C Type III (infibulation) involves the removal of all external genitalia, after which the wound is fused with cat gut, thorns or surgical threads (see [8, 9]). The clitoris may be pricked, pierced and scrapped to let blood in FGM/C Type IV. The practice represents the ritual of FGM/C in communities where FGM/C is outlawed ([10, 11]; for other forms of the practice, see [12, 13]).
\nAn estimated 200 million women and girls globally have undergone the FGM/C procedure, with populations with the highest percentages residing in Africa, including 1% in Cameroon, 4% in Ghana and Togo, and above 91% in Egypt and 98% in Somalia UNICEF [5]. In Europe, it is estimated that half a million women and girls are living with FGM/C [14], mostly due to the mobility of women and girls from countries that practice FGM/C [15, 16].
\nThe prevalence of FGM/C in Australia is difficult to determine, although some speculate that it has been around since 1994 [17]. Whilst there appears to be a lack of research and literature around FGM/C in Australia, the increase of migrants into the country from nations where FGM/C is practised may be an indication that FGM/C prevalence is increasing in Australia [18]. It is believed that women who have experienced FGM/C arrive in Australia after the procedure has been done [19]. Tellingly, statistical analysis shows that Australia received 38,299 migrants from 11 African countries where FGM/C is highly prevalent such as Sudan (24,082), Egypt (6258), Somalia (2736) and Ethiopia (5223), with the remainder from other African nations, as reported by Bourke [20, 21]. In 2010, the Melbourne Royal Hospital reported that it had seen 600–700 women living with FGM/C [20, 21]. Mathews [18] argues that the challenge of accurately establishing the prevalence and occurrence of FGM/C in Australia also stems from secrecy of the practice when compared to how it is symbolically portrayed in public ceremonies in countries that observe FGM/C (see also [16]).
\nA 2010 US survey revealed that sexual and reproductive healthcare professionals (SRHPs) may have knowledge about the presentation of FGM/C amongst migrants, but lacked culturally competent skills and adequate information to provide competent healthcare for women living with FGM/C [22]. Hess et al. [22] also found that negative attitudes and cultural insensitivity in SRHPs reinforce stigmatisation and isolation, resulting in poor sexual health amongst migrant women. Further, Berggren et al. [23] conducted a study in Sweden revealing that midwives attending to women living with FGM/C did not have adequate knowledge, which was evident during labour of women with infibulation. They also revealed that cultural insensitivity by healthcare professionals, poor cross-cultural communication and poor management of the labour process resulted in caesarean sections in women with FGM/C more often than was necessary.
\nZaidi et al. [24] found that there is a need for healthcare professionals working with women living with FGM/C to be aware of their own cultural prejudices that may affect the wellbeing of their patients. Other researchers investigating healthcare professionals’ knowledge and management of FGM/C revealed that cross-cultural training of healthcare professionals working with migrant women is imperative to address the knowledge gaps that hinder efficient service delivery to women living with FGM/C [25, 26]. Widmark et al. [27] suggested that the systematic involvement of infibulated women in pregnancy and birth planning frameworks could ultimately establish efficient service delivery and address knowledge gaps.
\nCultural competence amongst healthcare professionals working with women living with FGM/C can also decrease stigmatisation towards these women, ultimately leading to better health outcomes for them and their families [22]. Further, Zaidi [24] cited communication between the healthcare professionals and women living with FGM/C as a major drawback to the achievement of better health outcomes for women living with FGM/C in host countries. This study aimed to investigate the experiences of healthcare professionals providing sexual and reproductive healthcare to women living with FGM/C in Western Australia. A secondary aim of this study was to contribute to the wider body of knowledge regarding healthcare professionals working with women living with FGM/C in Western Australia.
\nThe WHO defines FGM/C to include ‘all procedures that involve partial or total removal of the external female genitalia or other injury to the female genital organs for non-medical reasons’ ([3], p. 3). FGM/C is performed on children between 0 and 15 years [28]. Traditionally, it is performed at 8 years of age on average but can occur at any age. Kolawole [29] argued that FGM/C is infused with cultural, legal and medical implications, making it difficult to adequately define. Debates regarding terminology and definitions continue across all societies, social groups and cultures. Almroth et al. [30, 31] pointed to concerns amongst scholars regarding the use of terminology and the ritual of FGM/C; in particular, some scholars consider ‘mutilation’ (p. 457) a medically acceptable term for the practice, as it involves the removal of healthy tissue and organs without medical indication, whilst others have argued that this term denotes negative connotations and attitudes towards the procedure, and may be offensive to some cultural groups [31, 32].
\nWe have argued elsewhere [33] that the term ‘female circumcision’ implies an analogy with male circumcision, which is misleading from an anatomical aspect as male circumcision only involves the removal of the glans, which by no means corresponds to the cutting of female genitalia (see also [31, 34])—FGM/C could only be compared with male circumcision if the penis were completely amputated and the surrounding tissue removed, as the cutting experienced by girls is severe, with irreversible effects that inhibit both sexual and reproductive capacities [29].
\nAccording to Bibbings [35], ‘female genital mutilation’ (p. 139–149) suggests torture and violent bodily injury forced on children and unwilling women by men and women from their cultural groups for the benefit of men and their communities or groups. This study shares this viewpoint, and both the term female genital mutilation and cutting (FGM/C) have been used concurrently to take a strong stand against the procedure, whilst acknowledging the theoretical debates on the definition of FGM/C as well as cultural, social and health implications of the procedure (see [36]).
\nSeveral scholars have argued that FGM/C is a strategy that exploits female sexuality for the sexual pleasures of men [37, 38, 39]. Some authors have postulated different reasons for the occurrence of FGM/C, including marriage [39], religion [26], cultural reasons [40], ethnicity [41], maternalism [23], patriarchy, and social pressures [37]. Additionally, community attitudes towards the continuance of the practice are reported to slow and frustrate measures designed to address and potentially end the practice [11, 42].
\nAccording to Almroth et al. [30, 31], there seems to be no known clinical studies that have documented the consequences of FGM/C, and the body of available literature only documents results of survey-based studies [30]. Anecdotal evidence and accounts of the consequences of FGM/C report a correlation between the procedure and adverse sexual and reproductive health outcomes [43]. Immediate and long-term sexual and reproductive health conditions have been reported in women living with FGM/C, although the severity of these conditions is believed to be dependent on the extent or the type of the procedure performed.
\nDiouf and Nour [44] argued that the adverse effects of Type I, Type II and Type III FGM/C can be short and long term, and possibly increase the risk factors for an HIV transmission due to the use of non-sterile instruments during the procedure. Wakabi [45] documented how surgical equipment is traditionally used numerous times on more than one initiate during the FGM/C procedure without being sterilised, increasing the risk of HIV and other blood-borne viruses (BBVs) being transmitted. Additionally, [46] argued that excessive bleeding is a complication of the FGM/C procedure, which can increase the need for medical attention (i.e., a blood transfusion); this may again increase the risk of potential HIV transmission. Although untraditional, it is based on adverse medical complications of FGM/C that the procedure came to into existence by emulating western medical practices of male genital cutting/circumcision (MGC/M).
\nThe medicalisation of FGM/C refers to any form of FGM/C being performed by healthcare providers, whether in private or public facilities, in the home or any other place where it may occur, in contrast to the traditional circumcision ceremony, which is usually ritualised and surrounded by public celebrations of the procedure [47]. In Kenya, for example, the medicalisation of FGM/C has become common amongst holidaymakers living in Western countries who originate from this country. Therefore, it is common amongst the Bagusii and the Kuria in the west of the country, where FGM/C is highly prevalent, and Njue and Askew [48, 49] reported that it has become common amongst nurses, midwives and even medical doctors to perform the procedure after consultations with a child’s parents.
\nHowever, we opine that the medicalisation of FGM/C raises moral questions pertaining to whether it is a measure to protect the sexual and reproductive health of girls and women or an imperialistic promotion of a dangerous practice [50, 51]. Furthermore, the minimisation of complications during and after the procedure raises questions as to whether the medicalisation of FGM/C reduces harm or perpetuates an extremely dangerous practice [38].
\nA decade ago, the WHO delivered a joint statement against the medicalisation of FGM/C on the basis that it excuses and perpetuates a harmful practice, and further stated that the medicalisation of FGM/C is a dangerous and criminal practice, requiring strategies to stop healthcare providers from carrying out the procedure [52].
\nThis project was designed as a qualitative study. According to Morse [53] and Sandellowski [54], qualitative research is particularly useful when collecting information about unknown topics, as it has the potential to provide rich and detailed descriptions of a phenomenon. The descriptive phenomenological approach in qualitative research was used as it can provide deep insights, as discussed by Liamputong [55, 56]. Phenomenology is an approach to qualitative research that seeks descriptions of phenomena and how they are experienced by the actors and is effective in bringing to the fore the perceptions and experiences of individuals from their own perspectives [57]. Phenomenology allows researchers to unearth lived experiences of individuals through narratives, whilst the research takes a neutral position with no preconceived ideas of what the outcome might be (see [58, 59, 60]). Lopez and Willis [61] also suggested that the phenomenological approach in qualitative studies can examine subjective human experiences by making enquiry efficient without bias and preconceived knowledge, attitudes and values, which must be shed by the researchers prior to conducting interviews.
\nPurposive sampling was applied as a time-saving technique, to avoid the process of searching for specific information in a potentially broad group of possible informants. Coyne [62] suggested that purposive sampling is the most appropriate method when detailed and abundant data are required to investigate a specific phenomenon [62]. Therefore, participants were chosen based on their experiences working with patients living with FGM/C who were seeking sexual and reproductive healthcare services. The research sample was drawn from different healthcare organisations across the Perth metropolitan area, all of whom worked in various sexual and reproductive healthcare organisations.
\nThe researchers also applied snowball sampling; six participants who met all the inclusion criteria were interviewed. The number of participants in this study was appropriate, as qualitative research does not seek to generalise but to seek and report on phenomena [63]. They ranged in age from approximately 25–60 years, with mean age of 39 years. The participants comprised four midwives, one nurse and one doctor. All worked for the government public health departments of both government and private sectors.
\nFace-to-face in-depth interviews were conducted at the participants’ place of employment. Interviews took 30–60 minutes and were conducted using semi-structured questions to guide the process and ensure relevant topics were covered. Participants were provided with a Participant Information Sheet and signed an Informed Consent Form before the interviews commenced. Signing the Informed Consent Form provided permission for the interview to be audio recorded. One joint group interview of four midwives and two individual interviews, one with a doctor and the other with a community nurse, were conducted. The joint interview was facilitated as participants had extreme time restrictions and the only available time could accommodate a joint interview comprising team members of the maternity ward department of a public hospital.
\nThe audio-recorded interviews were transcribed within 2 weeks of collecting the data, each line being numbered and printed to allow easy examination of the content. Data reduction was conducted after the transcribing and the data coded afterwards, allowing for the categorisation of emerging themes. The printed transcriptions were examined and constantly compared with the field notes to identify emerging themes. The initial analysis was open, allowing the researchers to develop hierarchal categories across all data sets, including the field notes, to find repeated patterns of meaning. This was followed by axial coding, which allowed the researchers to connect codes, thereby establishing the relationship between all codes [63].
\nOpen coding was initiated at the beginning of data analysis, with the researchers examining and colour-coding field notes to identify themes and then sequentially numbering all the lines in the transcribed interviews. In coding the data, Nvivo 10 and Microsoft Word were used. This study was approved by the Curtin University Research Ethics Committee.
\nAnis et al. [64] argued that placing patients at ease in an environment so they are able to speak about their FGM/C is a key to provide consistent care and positive outcomes. Participants expressed concerns regarding poor communication between their patients and themselves. The difficulties in communication were both verbal and non-verbal, which included the refusal by patients to respond to questions when asked if they lived with FGM/C. Participants reported that they also refused examinations when they presented at the sexual and prenatal clinics. This led to the late discovery of the presence of FGM/C in women who had presented with pregnancy and labour. The following excerpts are from the interviews conducted with the SRHPs:
\nThey don’t talk about it … but they don’t talk about it … they know what is happening to them … the very first one that I saw I was really shocked, because there was only an opening you could only let a finger in … she knew she had a problem … but she didn’t talk of what had happened to her …
\nAnother midwife made the following statement: ‘they would refuse all vaginal exams … they don’t tell anyone that it has been done to them … and they just arrive … here!’ Another participant commented:
\nWell … hopefully, that should be identified at the antenatal clinic … but as it goes … don’t tell us … if they refuse examination at the antenatal, which a lot of them do, we don’t find out until they are in labour …
\nThe professional health workers expressed how some of the patients were not aware of the FGM/C themselves, that it had been done when they were too young and that they may not have even known that they had it. One of them reported that she saw no need to talk about FGM/C with these patients. She also expressed her view that it was not her place to talk about FGM/C as she feared there could be implications in speaking about it with her patients. She expressed a deep lack of confidence in communication with her patients living with FGM/C:
\nI wonder if it is helpful for me to point out to them that they have a problem which is not in one of my problem categories … yeah … They would be as how they have always been … they won’t actually know any difference … I don’t know what intervention is of benefit … Maybe that is what I need to learn more about … what evidence is there towards intervention? … asking those questions is important but I don’t know how … but I do feel that even if someone says that, this is ok to talk about it … I can still get myself into a lot of trouble … and I think I … bring up a subject that is very sensitive and very difficult … that I actually don’t have very much skill to help with … then I would cause harm … and so often I won’t mention whether they may or may not perceive they have a problem is sometimes more harmful than good … and yet I recognise that I may be missing an opportunity … to discuss … but they may not have the courage to discuss …
\nParticipants reported that they felt inadequately equipped to communicate effectively with women living with FGM/C and suggested that healthcare professionals with the same cultural background as their patients would be appropriate to provide services to women living with FGM/C. It was also suggested that culturally specific healthcare to women living with FGM/C would promote efficient communication between healthcare professionals and their patients. A doctor made this statement:
\nI guess my thinking is that someone who is from the same culture or background would understand that background and would have more ability to … perhaps ask the right questions … so it is that sense of someone who understand me … so I won’t go to a man for a pap smear … someone who understands women’s health … I think the similar would be the case … to talk to someone who thinks this is barbaric … to do that to my daughter … how can I go to that person for help? I need to speak to someone who understands the background and the pressure …
\nAdditionally, participants reported that they were concerned about their patient’s capacity to comprehend the medical information and advice provided. One midwife expressed concern about the ability of the patients to clearly understand what was being communicated to them during service delivery:
\nI’m not 100% sure women will know what we are asking them … you know … have you been cut? … they may not understand what we are asking … and they may not have knowledge of what has been done … a youth worker … had FGM … and she didn’t know because she didn’t know how a normal vagina would look like … She didn’t know she had been cut … a doctor had to examine her to see if she had been cut.
\nAnother participant strongly emphasised the importance of efficient communication between patients and healthcare professionals: ‘Yes. Communication is the key.’
\nCommunication difficulties between participants and their patients were discussed by participants as barriers to efficient sexual and reproductive health service delivery. The reasons for these communication barriers were reported to stem from cultural conflict between healthcare professionals and their patients.
\nSeveral of the participants reported that they viewed the procedure of FGM/C in their patients as barbaric, incomprehensible, oppressive and dangerous and expressed sadness and anger at the pain that women with FGM/C have to endure during delivery. However, despite these feelings of sympathy, they experienced frustration, shock and anger that these women do not speak about FGM/C even when they are asked. A doctor made this statement:
\nit makes me sad that that happens … to people who don’t have the ability to step out of their culture … they don’t go, ‘Oh my God, we are cutting a baby on a sensitive area! That can’t be right!’ And yet, I have days I reflect on tradition and things that have been done for a long time … then there must be some reason behind it even though to my … outsider position I am looking at it, and it is completely wrong.
\nAnother participant stated:
\nThe sensitivity is of course related to sexuality; it is related to cultural identity and that whole sensitivity is multiplied by the fact that we are medical professionals from the other culture … And I think if it was my culture, I would feel I have the right to ask … in the same way a woman can ask a woman about periods and talk about sex in a way that a man doctor can’t ask that question … But I come from a different culture and I am asked questions about a practice that people from that culture, which is new to this country, they realise that the practice is forbidden and that there is overriding condemnation of it. And they may even feel that me asking a neutral question could sound like condemnation.
\nA midwife described with profound sadness how she witnessed a woman suffer during childbirth: ‘Oh, I was upset … when I saw the poor girl … I told you she had an opening only one centimetre. We couldn’t even find her urethra … It is very sad.’
\nAnother midwife was clearly psychologically disturbed by FGM/C in her patients:
\nIt makes me mad … it makes me very sad that the woman has had to endure it … especially if it was done in countries with basic tools … knives, and I think, that is a small child that it was done to and I … the pain and why you do it?
\nRe-infibulation occurs after childbirth and returns de-infibulated women back to the previous state of infibulation; it is argued to have no benefits (e.g., [51, 65]). Statements were made by participants that women requested re-infibulation after childbirth. One midwife described how a doctor carried out re-infibulations after birth, giving him a large clientele of patients who preferred his services, which is in contrast to the typical cultural practice of women who are living with FGM/C, who usually have a preference for female healthcare providers [22, 66]. This midwife said:
\nI know … when I worked at XXXX hospital, one of the doctors used to look after a number of Middle Eastern ladies because he spoke their language, and there was a high proportion of FGM/C in these ladies … and at one stage, I know he was sewing them back as they were … because they were requesting it … before he was talked to about all the legalities …
\nIn non-traditional rituals, as occurred in Western societies, clinicians who support the practice of FGM/C often perform re-infibulation, creating a situation where FGM/C is medicalised [18]. This has been highly controversial within the WHO [52], which has called for prosecutions of clinicians who perform FGM/C, in line with the rationale that there is no excuse whatsoever for the facilitation of any form of FGM/C by medical practitioners [52]. Whilst the campaign against FGM/C has been highly visible within the traditional locations where FGM/C is practised (e.g., sub-Saharan Africa), in Western countries, clinicians are still faced with poor training. A lack of access to and knowledge of clear clinical guidelines for the treatment of women living with FGM/C is evident, which may increase the likelihood of re-infibulation occurring [67, 68].
\nParticipants in this study described how some women would travel for long overseas holidays to perform re-infibulation and also have their newborn daughters circumcised. The following statements were made by participants:
\nXXXX hospital now refer women, any women who have had daughters, to social workers to ensure they don’t disappear for long to circumcise their daughters … and they are trying to introduce it here: any woman that has a female baby is followed up … they have training for social workers … because they have specific training … to ensure these women do not disappear for long periods of time so the same thing is not done on them.
\nAnother midwife made the following statement: ‘she had previous Type III FGM … and the social worker sent me an email saying, “Can you talk to her about it, she has got two daughters and we want to make sure she doesn’t cut them?”’
\nSome of the statements made by the participants identify the need for culturally specific sexual and reproductive healthcare to meet the needs of women living with FGM/C.
\nThe participants expressed the need for women living with FGM/C to have access to culturally specific healthcare, reporting that this was lacking in the public health system in Western Australia. Participants described how healthcare professionals find it difficult to understand the culture of FGM/C and therefore feel inadequate in their capacity to provide sexual and reproductive health services in an efficient manner to women living with FGM/C. A doctor expressed how culturally specific healthcare would minimise conflict in the relationship between women living with FGM/C and healthcare professionals by training professionals with a similar cultural background as the patients to provide efficient healthcare:
\nit is a specialised area and accessing specialised services is important by those people who are fairly trained to help … even within gynaecology, you wouldn’t refer them to any gynaecologist … just those who are more experienced, those who are more able to help. Psychologists would have very little experience within that area, counselling and some would be very well experienced … I think there needs to be more conversations about it, and probably more training by people who are very much from that culture and understand all the in’s and out’s. And then give good advice as to how someone who is not from that culture might approach the issue. Because within our own culture we have many ideas of healthcare, even within one culture every person is different. It isn’t helpful if doctors are trained to provide the wrong approach.
\nIt appears therefore that clinicians with experience and backgrounds where FGM/C is traditionally practised can offer invaluable support to women presenting with FGM/C at sexual and reproductive health services in Western Australia. These clinicians could be targeted for specialised training in numbers that can appropriately cater for sexual and reproductive health needs of women living with FGM/C.
\nAll participants stressed the importance of consistently screening pregnant women for FGM/C and clearly recording the information at the antenatal care stage before women go into labour. The participants stated that this could help prevent complications during childbirth, such as prolonged labour and unplanned caesarean sections and episiotomies. Routine screening and the correct use of information were reported to facilitate appropriate planning and the prevention of trauma during childbirth. However, it was reported that this was often hindered by women’s refusal to be physically examined and by the poor recording of information. This is exemplified in this excerpt from one midwife:
\nOne of the doctors is the one who usually do … the anterior cuts … they actually do cut where they have been stitched … the registrar would decide where the cut’s gonna [sic] be … exactly where they will be placed … someone came in labour and no one knew the woman had FGM … and then it is bit of panic, and what can we do … Type III – a baby is not gonna [sic] come out … normally, if it is Type III, you would do one cut up, and then two up that way, and then afterwards sew the edges … so that it is not bleeding … and then do construction work afterwards.
\nAnother midwife concurred, adding the following:
\nand this poor girl had to have three episiotomies … one anterior and two posterior, to get her baby out. Because the baby was pressing against her vaginal wall I guess … and it started opening that diameter … a centimetre … the baby was never going to come out, so she had three cuts! And we had to get one of our consultants to come and do the delivery, because she needed a lot of work, and repair work done … so she had to go to theatre to get everything repaired, and hopefully, next time she’d have another baby, she should’ve been ok.
\nThese experiences were also reported to affect other important medical procedures. A doctor expressed difficulties when conducting pap smear examinations on infibulated women:
\nso the first lady that I ever met … I was quite convinced that … that was what I was seeing … she had a very severe form of uterine prolapse … which sounds like shouldn’t have happened … cause she had been stitched all up … and when this lady came, I could see that she had been … eh … I am actually sure whether it would have been Type II or Type III, but certainly stitched together for the large part. So the pap smear was difficult … so I didn’t know whether to tell her that’s the reason or I didn’t know whether to tell her whether it is due to menopause … so it is not really not relevant to say why … so say sorry it hurts and I just do what I need to do.
\nCross-cultural training as evidenced in this data is a key to efficient services to women presenting to sexual and reproductive health services with FGM/C. SRHPs’ experiences of caring for women with FGM/C in Western Australia reveal many frustrations and difficulties of providing care for these women. Appropriate training and policy framework and clear clinical guidelines for the care of women living with FGM/C are imperative in meeting the special needs of these women. The value of adequate experience, knowledge and skills in this area cannot be overstated.
\nThe participants reported their concerns regarding the inadequate training available for working with women living with FGM/C. All of the participants stated that the existing training was inadequate and, additionally, that they were not provided with adequate time or support from their employers to participate. They also commented on the lack of an adequate curriculum. One participant said:
\nmore training would be useful … I know there is some training based in XXXX hospital … and I had an opportunity to do some of that training yesterday … and … I mean … it is important to do more training … sometimes I think training would make me understand this is Type II …
\nIt was also suggested by the participants that professionals who have backgrounds working with women living with FGM/C would be ideal if trained as peer educators for women living with FGM/C, improving the processes of service delivery. A doctor made this statement:
\nprobably more training by people who are very much from that culture and understand all the in’s and out’s … And then give good advice as to how someone who is not from that culture might approach the issue. Because within our own culture, we have many ideas of healthcare, even within one culture every person is different. It isn’t helpful if doctors are trained to provide the wrong approach …
\nOther participants stated the need for integrated curricula in tertiary and professional training courses for doctors and midwives to enable them to acquire adequate skills for addressing FGM/C in their practice. One participant commented that the training is extremely basic and only provides limited information on FGM/C:
\nI think focusing less on the types and pictures … and focusing more on the effects that it has on the women’s lives … and how we can talk to people about it, and how we can educate people … but it is more about what can we do … educating ourselves than rather just analysis of FGM … But the fact that a child is screaming … it makes me sad that they are living with it and the effects it has on people. It makes me want to know more and what can I do … I used to examine women but in this role I am currently doing antenatal care … which is why I need to know how to ask these questions.
\nAnother concern was expressed regarding the content of the existing training. It was reported that, for a long time, the same content has been delivered yearly, with nothing new incorporated. A midwife stated:
\nshe [the trainer] would come and talk to our staff, she would literally take you through the types … the medical side, and same thing every year … same PowerPoint presentation, every year. And you knew you were never gaining anything from it … every year, but the same thing … quite a number of years … probably five years … listening to the same thing … being delivered.
\nA midwife agreed and stated that, ‘It’s usually the same information … it hasn’t changed.’ Some of the participants also expressed the need to be provided with training opportunities and supported by their employers if they were to be well equipped to deal with FGM/C in their patients. One midwife said:
\nI used to be a staff development officer at XXXX hospital, and the staff are inundated with ‘you have to do this, you have to do that’ … (lack time for training), and plus you have to do your work …
\nThere is a need for healthcare policies to integrate appropriate modules in curricula for training healthcare professionals to facilitate efficient and appropriate service delivery to women with FGM/C. This has to be based on the cultural diversity in Western Australia and the larger Australian society.
\nThis study focused on the experiences of healthcare professionals providing sexual and reproductive healthcare to women living with FGM/C in Western Australia and aimed to contribute to the wider body of knowledge regarding healthcare professionals working with women living with FGM/C in Western Australia. Individuals reported both unique experiences and commonalities within the context of their interviews. SRHPs providing services to women living with FGM/C in Western Australia identified a gross lack of adequate training services capable of equipping SRHPs to expertly meet the needs of women living with FGM/C. Significant changes are required to provide adequate care for women living with FGM/C in Western Australia.
\nWe wish to acknowledge Curtin University’s School of Public Health where the original thesis that informed this paper was submitted. The work of Mr. Matt Tilley of Curtin University’s School of Public Health who supervised the original thesis is also acknowledged.
\nAneurysmal subarachnoid hemorrhage (SAH) is a complex condition with an intricate and poorly understood pathophysiology. Increasing evidence strongly suggests that neuroinflammation plays a critical role after SAH, but conventional anti-inflammatory treatments have failed to improve clinical outcome [1]. Clinical research on SAH has mainly focused on delayed cerebral ischemia (DCI); however, DCI does not encompass the entire spectrum of pathological and clinical manifestations of SAH [2, 3, 4]. Although cerebral infarction is associated with poor clinical outcome and death after SAH, a significant proportion of SAH patients without cerebral infarction suffer from cognitive deficits and mood disorders and a reduced ability for activities of daily living and working, even in the long term [5, 6]. The absence of a close correlation between DCI and functional recovery indicates an ongoing pathophysiological process has been overlooked in SAH. The failure of the recent major NEWTON 2 clinical trial, of sustained intraventricular release of nimodipine, is the latest in a series of unsuccessful phase 3 randomized controlled trials (RCTs) to improve clinical outcome after SAH and further reinforces the need to identify novel therapeutic strategies [7, 8].
\nNutrition is essential to human health, and appropriate nutritional support is currently considered a standard of care for critically ill patients. Malnutrition—including depletion of essential micronutrients—frequently occurs among critically ill patients and is associated with an increased risk of morbimortality [9]. However, the clinical relevance of key nutrient deficiencies in acute neurological illnesses has not been thoroughly investigated. EPA and DHA are essential constituents of endothelial and neuronal membranes, respectively, and also the precursors of key mediators involved in resolution of inflammation and endogenous neuroprotection [10, 11]. Although massive loss of brain DHA in SAH patients was first reported over 15 years ago, the pathological significance of this process and the role of inflammation resolution following SAH have largely been ignored [11, 12]. Therapeutic interventions aimed at stimulating inflammation resolution and recovering the homeostasis of the brain and other vital organs after SAH could improve patients’ functional outcome [13].
\nThis chapter provides an overview of the potentially harmful consequences of selective deficiency of omega-3 FAs on brain structure and function in SAH patients. Moreover, given the possible clinical relevance to SAH and the growth and rupture of intracranial aneurysms (IAs), we provide a detailed discussion of recent findings on the role of omega-3 FAs in resolution of inflammation, with a focus on brain homeostasis.
\nRemarkable progress in our understanding of the pathophysiology of acute inflammation has been achieved through basic science over the last 20 years. Resolution of acute inflammation is now considered to be an active biochemical process that is required to enable tissues to restore normal structure and function following an injury [14]. Interference with the resolution phase of acute inflammation may result in necrosis, chronic inflammation, fibrosis, and organ dysfunction. The resolution process is triggered at the beginning of inflammation by a temporal switch in lipid mediator classes, which is induced by cross talk between cells of the innate immune system and other cells in the inflammatory microenvironment [11].
\nA diverse range of biologically active pro-resolving and anti-inflammatory mediators are synthetized by complex pathways that involve several enzymes, including cyclooxygenase 2 (COX-2), cytochrome P450s and several lipoxygenases (LOX). The majority of these endogenous mediators are derived from the long-chain omega-3 fatty acids (FAs) EPA and DHA and are members of the specialized pro-resolving mediator (SPM) superfamily [15]. SPMs represent an essential biochemical interface between inflammation and tissue repair and regeneration. The resolution of inflammation is a highly orchestrated adaptive process that depends on both the availability of SPMs precursors and the efficiency of the related biosynthetic pathways.
\nEach endogenous lipid mediator is structurally distinct and possesses specific biological functions which have been extensively studied in diverse experimental models. EPA is the precursor of the E-series resolvins (RvEs), which contains four main mediators (RvE1-RvE3 and 18-HEPE). DHA is the precursor of the D-series resolvins (RvDs), which contains six mediators (RvD1-RvD6), as well as the protectins (PD1-PDX) and the maresins (MaR1-MaR2); DHA derivatives are also known as docosanoids [15].
\nSPMs are active at pico-nanogram ranges and exert pleiotropic actions at the inflammatory microenvironment. SPMs stimulate the clearance of bacteria, dead cells, and debris that is required during tissue repair. SPMs also reduce leukocyte transendothelial migration, platelet activation, and production of inflammatory cytokines, thus providing multi-organ protection. The maresins (macrophage mediators in resolving inflammation) exert potent phagocyte-directed actions that include phenotypic conversion of proinflammatory macrophages into macrophages that suppress inflammation and promote tissue regeneration [16]. Collectively, SPMs actively promote resolution of inflammation and recovery of tissue homeostasis [15]. Interestingly, resolution of systemic inflammation appears to have its counterpart in the CNS represented by different DHA-derived endogenous mediators (see Section 5.1).
\nThe biosynthetic pathways that generate SPMs are clinically relevant and have been comprehensively studied [15, 16]. Drugs that inactivate the enzymes involved in SPM biosynthesis, such as selective COX-2 inhibitors and certain LOX inhibitors, delay the return to homeostasis and are considered resolution antagonists. Importantly, selective COX-2 inhibitors were synthesized before the identification of inflammation resolution pathways and are currently widely used as anti-inflammatory agents. Aspirin and statins also modify COX-2 by acetylation and S-nitrosylation, respectively, which results in generation of longer-acting SPM R-epimers. Thus, aspirin and statins are resolution agonists [15, 16].
\nIncorporation and transport of omega-3 FAs have been comprehensively described; here, we focus on the clinically relevant aspects [10, 17, 18]. Several studies have consistently shown that in vivo conversion of alpha linolenic acid (ALA), the short-chain omega-3 FAs from vegetable origin, to its bioactive long-chain derivatives (EPA and DHA) is very low in humans. In addition, the metabolism of omega-6 and omega-3 FAs is tightly linked, and thus a high dietary intake of omega-6 FAs further reduce the conversion of ALA to EPA and DHA and their biological effects. The body has also a limited capacity to store long-chain omega-3 FAs; only very small amounts of EPA and DHA are present in adipose tissue, and the brain retains DHA for its own function. Thus, providing preformed EPA and DHA is the most efficient method of increasing the concentrations of EPA and DHA in plasma and tissues.
\nEPA and DHA are incorporated into different blood lipid fractions after absorption by the gastrointestinal tract or after release from intravenously infused fish oil-based lipid emulsions (FOLE). These lipid fractions reflect the diverse means by which FAs are transported in the circulation and execute their physiological functions. The fractions incorporated in the phospholipid coat of plasma lipoproteins and plasma nonesterified FAs (NEFAs) are considered transport pools. Notably, the NEFA pool seems to be the main DHA plasma fraction that supplies the brain. The NEFA pool also represents a direct source of FAs to cells for generation of SPMs, as this pool readily transfers to inflammatory tissue via edema formation [19]. The FAs fraction incorporated in peripheral blood mononuclear cells (PBMCs) represents a functional pool due to the crucial roles of PBMCs in inflammation.
\nThe EPA and DHA content of red blood cells (RBCs) membrane which can be quantified by a specific and standardized analytical procedure—the HS-Omega-3 Index® methodology—reliably reflects the omega-3 FAs content of several tissues [20]. This omega-3 index has been increasingly utilized as a surrogate marker of omega-3 status. Long-term intake of EPA and DHA is the main predictor of the omega-3 index, but other factors influence its variability. Acute supplementation of omega-3 FAs does not modify the omega-3 index, as expected given the long lifetime of RBCs (100–120 days). In terms of clinical relevance, strong inverse correlations have been observed between the omega-3 index and cardiovascular morbimortality, particularly sudden cardiac death, as well as depression [21, 22, 23].
\nMicrovascular inflammation is an early event in the pathogenesis of atherosclerosis and other inflammatory conditions and is inextricably linked to microthrombosis [24]. Eicosanoid metabolism and leukocyte-endothelial interactions are interrelated processes and in turn are major drivers of thromboinflammation [25, 26]. Inflammation stimulates eicosanoid synthesis and expression of cell-surface adhesion molecules through upregulation of the nuclear factor kappa B (NF-kB), a master transcription factor necessarily involved in the inflammatory response.
\nMost eicosanoids derived from the long-chain omega-6 FAs arachidonic acid (ARA), including prostaglandins, leukotrienes, and thromboxanes, are potent vasoconstrictors, platelet activators, and leukocyte chemotactic factors. Moreover, the expression of cell-surface adhesion molecules on endothelial and inflammatory cells is essential for leukocyte-endothelial interactions; rolling and adhesion on vascular surfaces are the first step in the recruitment of circulating leukocytes or platelets to sites of thromboinflammation [27].
\nEPA incorporated in the membrane phospholipids of inflammatory cells can modulate eicosanoid metabolism by replacing ARA as an eicosanoid precursor [25]. EPA-derived eicosanoids are significantly less potent than those derived from ARA, and nonesterified EPA can also directly inhibit the production of eicosanoids from ARA. In addition, EPA has been shown to decrease the expression of several cell-surface adhesion molecules on inflammatory cells. EPA appears to elicit these pleiotropic effects by modulating the activity of the NF-kB.
\nAdditionally, recent mechanistic studies have shown that minor changes in the EPA content of endothelial membranes may markedly alter the biophysical properties of the membrane [28]. Furthermore, changes in membrane fluidity, thickness, and deformability induced by modifications to lipid dynamics and/or structural organization can profoundly impact endothelial function [29]. Given the intimate association between brain capillary pericytes and endothelial cells, it would not be surprising if EPA also incorporates into pericyte cell membranes and potentiates the function of these cells as regulators of brain homeostasis [30, 31].
\nDHA is widely distributed throughout the human body in membrane phospholipids and is particularly abundant in neural tissues such as the brain and retina [10]. DHA represents 30–40% of the fatty acid content of the gray matter in the cortex and is absorbed into the brain by a specific transporter that is found in the endothelium of the blood-brain barrier (BBB) microvasculature [32, 33]. The functional significance of selective enrichment of DHA in neural tissues has been actively researched over the last few decades. DHA possesses unique biophysical and biochemical characteristics that make it particularly suitable for brain and retinal membranes. DHA has been highly conserved during evolution and is present throughout the entire spectrum of living organisms [34]. DHA has even been suggested to be a major determinant for evolution of the modern hominid brain due to its unique encephalization potential [35].
\nDHA is an essential component of neuronal membrane architecture and composition and promotes selective accumulation of phosphatidylserine (PS), a crucial phospholipid involved in intracellular signaling [36]. PS participates in the signaling events of several key enzymes, including protein kinase C, Raf-1 kinase, and Akt, which play essential roles in cell proliferation, differentiation, and survival. Thus, DHA significantly modulates the activity of essential cellular kinases in neuronal cells.
\nIn addition to its function as a unique building block of cell membranes, DHA is also a precursor for docosanoids and other bioactive endogenous derivatives in the neural tissue [37]. The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38, 39, 40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37, 38, 39, 40, 41]. In addition, the DHA derivatives exert a range of potent neuroprotective properties that include inhibition of proinflammatory gene expression and leukocyte infiltration. A striking hallmark of the DHA derivatives is their ability to potentiate microglial polarization from a proinflammatory phenotype to a surveillance-repair state and reduce NF-kB-mediated expression of inflammatory cytokines in the brain. Moreover, DHA derivatives contribute to BBB integrity and are neurogenic and synaptogenic [38, 42]. Thus, the DHA derivatives seem to be key mediators of the resolution of inflammation and recovery of homeostasis in the CNS microenvironment.
\nThe concept of neurovascular unit emphasizes the intimate relationship between the brain and its vessels, particularly the coupling between neural activity and cerebral blood flow [43]. Although the role of DHA neurolipidomics in neurovascular coupling appears to be underestimated, substantial experimental evidence suggests that the morphologic and functional integrity of the neurovascular unit largely depends on high DHA enrichment [37, 40, 43]. Moreover, the potential role of EPA in microvascular function further supports the evolutionary importance of these essential nutrients to maintain efficient functional couplings between neural and vascular networks [28, 29]. A functional neurovascular unit may be crucial not only for neurovascular coupling but also for BBB integrity and neurogenesis.
\nA regular dietary supply of DHA is required to preserve normal brain and retinal function. Under physiologic conditions, the net DHA incorporation rate for the entire human brain is very low and equivalent to the net rate of DHA consumption by the brain (3.8 ± 1.7 mg/day) [44]. However, loss of DHA in pathological states or due to nutritional deficiency of omega-3 FAs may severely impair neurovascular integrity and have far-reaching implications on normal brain function [36].
\nTo date, three clinical studies have examined the loss of DHA from the brain after SAH. Pilitsis et al. conducted the first observational study to analyze free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) [12]. The concentrations of ARA, DHA, linoleic acid, myristic acid, oleic acid, and palmitic acid were measured over the first 14 days following SAH in 20 patients. A cohort of 73 patients with no evidence of acute neurological disease served as the control group. Compared to control patients, the concentrations of all FFAs tested were significantly elevated in CSF during the first 2 days after SAH, with a significant secondary increase in FAA concentrations at 8–10 days. The concentrations of DHA exhibited a biphasic increase and remained significantly elevated (200–600%) throughout the first 14 days after SAH.
\nIncreased levels of free DHA in CSF after SAH are likely to be the result of the cleavage of DHA from membrane phospholipids by either direct structural damage or an increase in phospholipase A2 activity in response to neuroinflammation. DHA can also be readily oxidized due to its high degree of unsaturation and excessive generation of free radicals following SAH [45]. Such nonenzymatic oxidation of DHA generates F4-neuroprostanes (F4-NPs), which represent a lipid marker of oxidative stress in the CNS. Two clinical studies confirmed that the concentrations of F4-NPs in CSF significantly increased within the first 24 hours following SAH compared to control patients [46, 47]. Hsieh et al. also showed the concentrations of F4-NPs in CSF remained significantly elevated throughout the first 10 days after SAH and suggested a positive correlation exists between F4-NP concentrations and clinical outcome at 3 months after SAH. Despite the limited number of patients analyzed, these studies provided valuable evidence that substantial loss of brain DHA occurs after SAH.
\nMoreover, it is highly likely that SAH may increase metabolic consumption of DHA though increased generation of neuroprotective derivatives. This potential additional source of DHA loss has not yet been evaluated but could be significant. Net cumulative DHA loss from the brain (DHA loss + DHA consumption) following SAH may be massive in some cases and is likely to impose a severe burden on the brain.
\nA current Western diet may provide sufficient amounts of FAs to compensate for the loss of other FAs, but not DHA. Current Western diets are characterized by very low intakes of long-chain omega-3 FAs and high intakes of other FAs, especially omega-6 FAs such as ARA and linoleic acid [48]. Thus, a significant imbalance between brain DHA loss and inadequate nutritional intake of omega-3 FAs may persist over the long term in SAH patients, hindering the recovery of DHA accretion in the brain required for normal neuronal function [35, 36].
\nLoss of EPA after SAH has not yet been examined; however, it is reasonable to assume that depletion of EPA from cerebral endothelial membranes may play a significant role in microvascular dysfunction after SAH. Indeed, EPA seems to have a more potent effect than DHA in the treatment of mood disorders, though the underlying mechanisms remain elusive [22].
\nWe coined the term “selective brain malnutrition” to describe the pathological consequences of EPA and DHA loss following SAH on the structure and function of the brain. This novel hypothesis of selective brain malnutrition offers a plausible explanation for some of the intriguing clinical features of SAH, including diffuse cerebral atrophy and the frequently observed long-lasting functional sequelae, such as cognitive dysfunction and mood disorders, that occur even in the absence of focal injury [5, 49]. Importantly, a higher omega-3 index has been associated with larger total brain and hippocampal volumes in observational studies in humans [50].
\nConsensus has emerged on the pressing need to find a multipronged therapeutic intervention to address the various deleterious effects of early brain injury (EBI) after SAH [51]. Nonetheless, the loss of brain DHA after SAH is likely to be an unrecognized effect of EBI, and in turn loss of DHA may represent a critical event in the pathogenesis of secondary brain injury after SAH. Depending on the severity of SAH, the cumulative burden of brain DHA loss may be massive and decreases endogenous neuroprotective capacity in the short term [12, 36]. Thus, unresolved homeostatic disturbances within the cerebral microenvironment may lead to neurovascular uncoupling, which may spread over the cerebral cortex in the most severe cases [52]. The loss of an entire series of signaling events required for maintenance of neurovascular network integrity may further increase the risk of focal injury, diffuse cerebral atrophy, and functional sequelae [37]. In this context, it is reasonable to assume that large-artery vasospasm may paradoxically be a compensatory mechanism to preserve tissue oxygen availability in the presence of progressive microvascular failure, i.e., when capillary transit time heterogeneity substantially increases [3, 31]. Unresolved inflammation may also induce hyperproliferation of arachnoid cap cells, which increases the risk of hydrocephalus [4]. Uncontrolled systemic complications, such as severe cardiopulmonary dysfunction, may further aggravate homeostatic disturbances and have devastating consequences on brain function [53].
\nTheoretically, EPA, DHA, and their respective SPMs possess the bioactive capacity to counteract the major homeostatic disturbances that occur after SAH. EPA-RvEs could reduce thromboinflammation at the cerebral microvasculature by inhibiting vasoconstriction, leukocyte transendothelial migration, and platelet aggregation [15, 26]. DHA and its derivatives may trigger the critical signals required to maintain functional neurovascular coupling and cell survival [16, 36, 37]. DHA-induced upregulation of the enzyme heme oxygenase 1 (HO-1) may accelerate the clearance of subarachnoid clots and thus decrease heme-induced cerebral inflammation [54]. SMPs may attenuate inflammation-induced hyperproliferation of arachnoid cap cells, further contributing to diminish the risk of hydrocephalus. SPMs may also provide multi-organ protection and enhance the immune response against infections.
\nFurthermore, the promising role of DHA derivatives in reducing microglial polarization toward an inflammatory phenotype may offer a novel approach to reduce the brain inflammation induced by neurosurgical trauma in surgically treated SAH patients [55]. Neurogenesis has also been identified in SAH patients, and thus DHA could represent a novel therapeutic strategy to improve neurological recovery by stimulating neurogenesis [56]. Moreover, subtle changes on microvascular function and synaptogenesis induced by EPA and DHA may improve cognitive function and mood and thus increase the likelihood of complete functional recovery of SAH patients.
\nThe theoretical framework described above provides scientific rationale for future clinical trials of omega-3 FAs in SAH patients. The disappointing results of RCTs of isolated pharmaceutical interventions in SAH could be overcome if a translational approach is correctly implemented [8]. In support of this notion, the recently published phase 3 REDUCE-IT trial provided a robust demonstration of the clinical efficacy and therapeutic potential of EPA to reduce cardiovascular events in chronic cardiovascular (CV) patients with hypertriglyceridemia [57]. Obviously, there are major differences between patients with chronic CV disease and hypertriglyceridemia and patients with SAH. Nevertheless, the considerable clinical benefits of EPA observed in patients with CV disease (who were already on statin therapy) may be due not only to the triglyceride-lowering effect of EPA. Interestingly, the results of the REDUCE-IT trial resemble those of the GISSI-Prevenzione trial conducted 20 years ago, in which a low-dose oral treatment of EPA plus DHA significantly reduced CV morbimortality in patients who had suffered a recent myocardial infarction and were already on aspirin treatment [58].
\nMinor changes in overall membrane FAs composition and the increase in local production of longer-acting SPM R-epimers after combined treatment with omega-3 FAs and aspirin or statins are likely to mediate a wide variety of biological effects and have a profound impact on cellular and multi-organ function [15]. Indeed, emerging evidence clearly indicates a strong association between a higher omega-3 index and major health benefits (reduced risk of both CV and all-cause mortality) over the long term [21]. However, the acute and critical nature of SAH imposes a particularly demanding therapeutic challenge as the homeostatic disturbances in the brain and other vital organs must be effectively addressed in the short term. An intervention based exclusively on oral supplementation with omega-3 FAs is unlikely to be fully effective on its own in the clinical context of SAH. However, the superiority of parenteral administration over oral or enteral administration of omega-3 FAs has been reliably demonstrated in short-term interventions [17, 59]. Parenteral administration of omega-3 FAs allows rapid delivery of higher doses of EPA and DHA without bioavailability issues and does not depend on the patient’s clinical condition. Indeed, the incorporation profiles of EPA and DHA in the transport and functional pools after a single parenteral dose are equivalent to up to several weeks of oral supplementation. EPA and DHA appear in PBMCs as rapidly as 6 hours after a single parenteral dose, thus highlighting the ability of parenterally administered omega-3 FAs to easily reach the innate immune system [59]. The concentration of omega-3 FAs in the main plasmatic fraction that supplies the brain and other vital organs (the NEFA pool) also increases rapidly after a single parenteral dose [17, 60]. Thus, the SPM precursors EPA and DHA seem to be rapidly and widely available to activate resolution of inflammation on demand in different organs after parenteral administration. Therefore, parenteral administration may be the most efficient way to deliver omega-3 FAs during the acute stage of SAH. This novel therapy is in accordance with the concept of pharmaconutrition, in which key nutrients are utilized as pharmacological agents and delivered in appropriate doses via the most efficient administration route [61]. Oral or enteral administration may be suitable for medium- or long-term treatment when the patient’s gastrointestinal function has completely recovered.
\nA regular supplementation dose for healthy subjects defined by several health associations worldwide is around 500–750 mg/day of EPA plus DHA and can be achieved by consuming a regular diet that contains two portions of fatty fish per week [62]. Therapeutic anti-inflammatory doses of EPA plus DHA are usually considered to be above 2 g/day [25]. A daily dose of at least 1 g EPA plus DHA/day (EPA > 60% DHA) has been shown to be effective in patients with depressive disorders [22]. EPA doses above 1.8 g/day seem to be required to produce clinically meaningful effects on endothelial and vascular function [63]. In patients with age-related cognitive decline, 900 mg DHA/day improved learning and memory function [64]. Importantly, omega-3 FAs doses can be significantly reduced by decreasing the dietary intake of omega-6 FAs. This fact likely explains the notably different dosages of EPA required to obtain beneficial outcomes in patients with chronic CV disease in a Japanese trial (1.8 g/day) and the REDUCE-IT trial (4 g/day) conducted in 11 Western countries [48, 57, 63].
\nThe therapeutic dose of parenteral fish oil (FO) to complement total parenteral nutrition (TPN) is of 0.1–0.2 g of FO/kg/day [59]. This dosage is equivalent to 1–2 ml/ kg/day of a specific FOLE that contains 10 g of FO/100 ml.
\nBioavailability refers to both the speed of absorption and the quantity of the substance absorbed in the gastrointestinal tract. The bioavailability of omega-3 FAs oral formulations should be carefully considered as it may have direct clinical implications [65]. The bioavailability of EPA and DHA depends on the chemical form in which they are bound (phospholipids > triglycerides > free fatty acids > ethyl esters) as well as their Galenic form (i.e., microencapsulation, emulsification) and also matrix effects (capsule ingestion with concomitant content of food, fat content in food). Galenic form and matrix effects are the most important factors that influence the bioavailability of EPA and DHA. Thus, administration of high-quality pharmaceutical formulations with fatty meals is necessary to ensure the effectiveness of oral therapy.
\nTo date, only two preclinical studies of omega-3 FAs in experimental models of SAH have been published. Yin et al. suggested that pre-treatment with omega-3 FAs by oral gavage elicited anti-inflammatory and anti-apoptotic effects in a rat model of SAH [66]. Zhang et al. showed intravenous administration of DHA may prevent oxidative stress-induced apoptosis by improving mitochondrial dynamics in a rat model of SAH induced by endovascular perforation [67]. However, the scarcity of preclinical studies on omega-3 FAs in SAH contrasts with the large number of experimental studies on ischemic stroke. The effects of omega-3 FAs (or specific derivatives) in neural tissue have been widely examined in experimental ischemia-reperfusion models [55, 68, 69]. These studies have consistently shown that omega-3 FAs significantly reduce cerebral infarction volume by around 40–50% and are associated with a drastic decrease in the neuroinflammatory response [70, 71]. Interestingly, the long-term neurobehavioral recovery in experimental models of ischemic stroke is associated with neuroprotective effects of DHA on both gray and white matter [55]. It is noteworthy that one of these studies used a specific FOLE that is widely approved for clinical use [70].
\nA limited number of omega-3 FAs interventional studies have been performed in SAH patients [13, 72, 73, 74]. The main characteristics and findings of these studies are summarized in Table 1. Two studies utilized EPA and DHA, and only one study included a parenteral regimen. In total, 229 patients with SAH have received an omega-3 FAs intervention; most patients were surgically treated (
Reference | \nType of study | \nPopulation, | \nIntervention | \nMain result | \n
---|---|---|---|---|
Yoneda et al. [73] | \nProspective, non-randomized | \n\n EPA = 73 | \nOral EPA: 1800 mg/day × 10 postoperative (PO) days | \nReduction in vasospasm and cerebral infarction | \n
Yoneda et al. [74] | \nRCT | \n\n EPA = 81 | \nOral EPA: 2700 mg/day × 30 PO days | \nReduction in vasospasm and cerebral infarction | \n
Nakagawa et al. [72] | \nRetrospective study | \n\n EPA + DHA = 55 | \nOral EPA: 1860 mg/day + oral DHA: 750 mg/day × 90 PO days | \nReduction in vasospasm and cerebral infarction | \n
Saito et al. [13] | \nPilot RCT | \n\n EPA + DHA = 20 | \nParenteral perioperative: 5 days Oral EPA: 1840 mg/day + oral DHA: 1520 mg/day × 8 weeks | \nNo postoperative intracranial bleeding complications Easy-to-implement intervention | \n
Summary of the features and outcomes of clinical interventional studies in SAH patients.
Evidence obtained over more than two decades in other clinical fields indicates omega-3 FAs interventions are unlikely to lead to serious clinical harm in SAH patients [25, 59]. Nevertheless, parenteral administration of omega-3 FAs may raise some safety concerns. Total parenteral nutrition is associated with an increased risk of complications in critically ill patients [9]. Furthermore, administration of lipid emulsions (LEs) may cause fat overload syndrome; the amount of fat administered and LE infusion rate are the primary risk factors. In this regard, it should be emphasized that the therapeutic dose of FO (0.1–0.2 g of FO/kg/day) is about one order of magnitude lower than that of regular LE (0.7–1.5 g of fat/kg/day) [59]. Additionally, the plasma clearance rate is faster for FAs administered in FOLE than soybean oil-based LEs. These unique features contribute to the good safety profile of FOLE. Fish oil has been widely used as a component of total parenteral nutrition and is associated with reduced rates of infection, shorter hospital stay, and decreased mortality, particularly in surgically treated patients [59].
\nFurthermore, isolated parenteral administration of FO has increasingly been used in pediatric patients with parenteral nutrition-associated liver disease (PNALD). Several case series published since 2006 have reported parenteral FO monotherapy (PFOM) remarkably improved clinical outcome of patients with PNALD [75]. Importantly, PFOM has demonstrated a good safety profile in these critically ill patients, even at FO doses up to 1.5 g FO/kg/day and overextended treatments beyond 4 weeks, well beyond the manufacturer’s recommendations.
\nThe aim of replacement FO therapy in PNALD is obviously different to SAH patients. Parenteral administration of FO is intended to address key nutrient deficiencies during the acute stage after SAH, and thus only short-term administration of a regular FO dose should be necessary. In fact, a 5-day parenteral perioperative regimen did not increase the occurrence of major postoperative complications in 19 surgically treated SAH patients [13]. Thus, there is good quality evidence to warrant further clinical trials of parenteral pharmaconutrition as an integral component of interventions with omega-3 FAs in SAH patients.
\nThe role of inflammation in the growth and rupture of intracranial aneurysms (IAs) has been increasingly recognized over the last few decades; however, the specific role of resolution of inflammation in IAs has not yet been considered [76]. Although the pathophysiology of atherosclerosis and the growth and rupture of IAs are distinct, both conditions are mediated by an underlying inflammatory process [77]. The progression of atherosclerotic plaques determines plaque morphology and the risk of rupture. The degree of macrophage infiltration plays a crucial role in the progression of atherosclerotic plaques. Interestingly, IAs have also been recently regarded as a macrophage-mediated inflammatory disease in which prostaglandin E2 and the master transcription factor NF-kB may be crucial drivers of inflammatory signals [78, 79]. It should be remembered that prostaglandin E2 is derived from the long-chain omega-6 FAs ARA and that EPA can inhibit the generation of eicosanoids from ARA and also downregulates the activity of NF-kB [25].
\nAtherosclerotic plaques readily incorporate omega-3 FAs, and a higher plaque EPA content is associated with a reduced number of foam cells and macrophages, as well as increased plaque stability, as determined by a well-formed fibrous cap [80]. Additionally, signs of defective resolution of inflammation have been identified in atherosclerotic plaques [81]. One major function of SPMs (particularly maresins) is to induce phenotypic conversion of macrophages, which decrease inflammation and promote tissue regeneration [16]. In animal models of atherosclerosis, a traditional Western high-fat diet disrupts the homeostasis of inflammation resolution by nutrigenetic modulation of the 12/15-LOX pathways, thereby inhibiting the generation of protective SPMs [81, 82]. These recent findings in atherosclerosis, particularly the involvement of docosanoids in vascular inflammation, provide biological plausibility that defective resolution of inflammation is implicated in the pathogenesis of IA growth and rupture.
\nHuman beings evolved, and their genetic patterns were established on a diet with an omega-6/omega-3 FAs ratio of 1/1, whereas in current Western diets, this ratio is around 16/1 [83]. Thus, this extreme nutritional imbalance in current Western diets should be seriously considered as a potential aggravating factor for the growth and rupture of IAs [48, 82]. This suggestion may appear somewhat counterintuitive considering the high prevalence of IAs with increased risk of rupture in the Japanese population, which has one of the highest dietary intakes of omega-3 FAs worldwide [48, 84]. However, nutritional deficiency of long-chain omega-3 FAs may not be the only factor associated with defective resolution of inflammation. Inter-individual and ethnic variations in the susceptibility to IA growth and rupture could be related to tissue-specific enzymatic deficiencies in the biosynthetic routes that regulate the resolution of inflammation. However, while defective resolution has already been associated with other chronic inflammatory diseases, it is not yet known whether enzymatic deficiencies contribute to IA growth and rupture, and this novel hypothesis requires further investigation [85, 86].
\nThe vital roles of EPA and DHA in the human body emphasize the evolutionary importance of maintaining efficient functional couplings between chemical and biological systems as well as between the vasculature and the brain [87]. Resolution of inflammation and endogenous neuroprotective signaling are interrelated processes that largely depend on EPA and DHA derivatives. This novel concept may open new avenues for public health interventions and innovative research in IAs and SAH.
\nAlthough nutrition has been traditionally viewed as a supportive measure, increasing evidence strongly suggests that a more balanced dietary intake of omega-6 and omega-3 FAs may represent the most efficient means of improving the status of inflammation resolution at the population level [48, 82, 83]. This specific dietary recommendation could contribute to decrease the risk of IAs growth and rupture and the devastating consequences of SAH, along with other important health benefits.
\nThe pathological significance of the loss of brain DHA after SAH has been widely ignored, even though strong preclinical evidence supports the hypothesis that the integrity of the neurovascular unit largely depends on high DHA enrichment. This previously unrecognized pathophysiological process may significantly increase the risk of secondary brain injury following SAH.
\nThe robust demonstration of the clinical efficacy of EPA in patients with chronic CV disease supports the encouraging results obtained in preliminary clinical studies of omega-3 FAs in SAH and warrants a large-scale RCT. It needs to be emphasized that DHA should always be included in neuroprotective interventions, as DHA plays an essential role in neural tissue and is the cornerstone for docosanoid generation. Parenteral pharmaconutrition with FO offers major clinical advantages for the treatment of SAH patients and should also be an integral component of omega-3 FAs interventions during the acute stage of the disease.
\nThe design of future RCTs of omega-3 FAs in SAH should bear in mind a potentially important factor. Clinical approaches that mainly focus on large-artery vasospasm may actually counteract the beneficial effects of omega-3 FAs and other neuroprotective interventions. The main rationale behind this seemingly paradoxical notion is based on both theoretical models and clinical perspectives [3, 31]. An unpublished subgroup analysis of our pilot pharmaconutrition trial of omega-3 FAs showed unexpected differences in the occurrence of cerebral infarction due to DCI between study centers, each of which had different clinical approaches to large-artery vasospasm [13]. In addition, a recently published observational study performed in the UK showed centers that screened for large-artery vasospasm using transcranial Doppler ultrasound (TCD) had poorer inhospital outcomes and similar rates of DCI diagnosis compared to centers that did not [88]. These results support the dissociation between large-artery vasospasm and clinical outcome that has been observed in major phase 3 RCTs in SAH [8]. Therefore, reliance on a surrogate clinical endpoint such as large-artery vasospasm may lead to the adoption of useless or even harmful clinical approaches [88, 89, 90, 91]. Indeed, some research centers in Europe do not include TCD ultrasound or endovascular rescue therapy in their treatment protocols for SAH patients [92].
\nMoreover, it would be clinically meaningful to determine if correlations exist between the omega-3 index and the concentrations of EPA and DHA as well as the status of inflammation resolution in the wall of ruptured and non-ruptured IAs. There may be a real opportunity for a readily implementable and low-cost therapy if the walls of IAs are as responsive to omega-3 FAs as atherosclerotic plaques.
\nThe interplay between omega-3 FAs and widely used drugs (aspirin and statins) that lead to the generation of longer-acting SPM R-epimers provides ample opportunities for future translational approaches in IAs and SAH. Indeed, combined therapies with omega-3 FAs and aspirin or statins could represent a viable, easy-to-implement therapeutic strategy for patients with unruptured IAs.
\nParenteral pharmaconutrition with FO could also be a clinically effective intervention for perioperative neuroprotection for patients subjected to other surgeries at high risk of neurological injury, such as carotid endarterectomy, cardiac surgery, or diverse neurosurgical procedures.
\nIn the future, new drug delivery systems capable of carrying synthetic analogues of SPMs could become a viable therapeutic strategy for patients with tissue-specific enzymatic deficiencies in the resolution pathways [93].
\nThe authors have no conflicts of interest to declare.
We express our appreciation to our patients from whom we have learned so much.
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