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A Commentary on “The Criminalization of Womenwith Postpartum Psychosis: A Call for Action forJudicial Change”

DOI: 10.31038/AWHC.2024742

   

Postpartum psychosis is a unique and serious mental health challenge. Women are more vulnerable to mental illness surrounding childbirth due to genetic, hormonal and psychosocial factors. The most severe form of postpartum mental illness, postpartum psychosis affects 1 to 2 of 1,000 women or 4,000 or more women in the U.S. each year (Friedman et al.2023; Griffen 2023; Perry et al. 2021; Postpartum Support International: PSI statement on psychosis related tragedies 2004; VanderKruik et al. 2017). These mothers are at an increased risk of suicide (4 to 5 percent), and infanticide, neonaticide and filicide (1 to 4 percent). For 40 to 50 percent of those with postpartum psychosis, this is a first occurrence with no prior history of mental illness (Friedman et al. 2023; Griffen 2023; MGH Center for Women’s Mental Health: Reproductive Psychiatry Resource & Information Center 2018; Perry et al. 2021; Postpartum Support International: PSI statement on psychosis related tragedies 2004). To prevent tragic outcomes, mothers with postpartum psychosis or severe depression with psychotic features require crisis intervention, immediate hospitalization and psychiatric treatment.

The article, “The criminalization of women with postpartum psychosis: a call for action for judicial change,” published in the Archives of Women’s Mental Health, promotes postpartum criminal laws in the U.S. and abroad when criminal culpability is linked to maternal mental illness. Similarly, it is essential to include postpartum psychosis as a diagnostic criteria and classification in the Diagnostic and Statistical Manual of Mental Disorders (DSM) (American Psychiatric Association 2013; Spinelli 2021).

These changes would have enormous influence in trial and sentencing when homicide cases are a consequence of maternal mental illness.

In the U.S., the judicial system has not utilized the advancements and growing body of scientific developments regarding reproductive mental health in the last decades in psychiatry and medicine. This is evident when women with postpartum mental illness are prosecuted. In more than thirty countries worldwide, there is treatment, rehabilitation and mitigation when women commit infanticide as a consequence of psychosis and severe postpartum mental illness in the year following childbirth.

In 1938, the U.K. emphasized treatment and prevention over punishment (Infanticide Act 1938) by adopting laws safeguarding mothers suffering from postpartum depression or psychosis. Currently in the U.K and many other countries, a woman who causes the death of her child within 12 months of delivery is presumed to be mentally ill.

In the U.S., Illinois is the only state that considers maternal mental health as a factor in cases of infanticide. Public Act 100–0574 signed into law in January 2018 and amended in 2019 by PA 101– 411, recognizes postpartum depression and postpartum psychosis as mitigating factors to be considered in trial and sentencing. This law allows women who are currently incarcerated to file for resentencing and allows consideration of postpartum mental illness in past, present and future cases.

It is essential to prioritize awareness and prevention of postpartum mental illness to save the lives of mothers and babies. We must enact comprehensive postpartum laws in every state to address screening and treatment as well as to consider mental health as a mitigating factor when unrecognized and untreated mental illness leads to tragedy and involvement with the criminal justice system. The time is NOW to enact postpartum criminal laws and judicial change throughout the U.S. and abroad.

Building Research Collaboration Across University Departments: A Swot Analysis

DOI: 10.31038/IJNM.2024544

Abstract

Purpose: To challenge the collaborative process in a young research team with evidence on building research collaboration in university departments.

Methods: A structured literature review was combined with a hermeneutic analysis of data from a double survey conducted during a one-week seminar. Eight Norwegian participants provided data through a Strengths, Weaknesses, Opportunities, and Threats (SWOT) template.

Results: The literature review revealed two themes 1) Building a research network, and 2) Networking across university units. A naïve reading of the double survey data showed that participants enjoyed collaborating in research networks. A structured interpretation provided a contextual report on collaborative research processes across university units working to build research collaboration.

Conclusion: Excellent research collaboration emerges through focus, flexibility, trust, persistence, and leadership. A successful research group is dependent on positive engagement between members, the acknowledgment of individual contributions and ideas; and supportive team leadership which is especially facilitated through dialogical leadership.

Keywords

Hermeneutic analysis, Literature review, Leadership, Competence development, Qualitative, SWOT

Introduction

Research collaboration refers to “the working together of researchers to achieve the common goal of producing new scientific knowledge” [1]. In this context, occupational professionals who work in research and development are strategically managed [2] to improve knowledge transfers through transformational leadership [3]. This process is critical, as research collaboration is fundamental to scholarly research success. However, it is often difficult to build a collaborative research team [4]. To clarify the characteristics of such an endeavor, this study reviewed the literature on building collaborative research teams, then compared the results using a collaborative process experienced by a young, publicly funded healthcare research team that spanned multiple university units.

Background

Our initial literature review yielded 443 articles, of which we retained 394 after removing duplicates (Figure 1). Two of the authors then conducted independent screenings, resulting in 23 for potential inclusion. After reviewing the full texts of each, the authors excluded 15 for focusing on collaboration between international teams or separate universities rather than intradepartmental collaboration. Thus, the final sample contained eight articles, with various settings in the United States, Canada, Greece, the United Kingdom, and Ireland. One article introduced a new method for developing strategic research plans [5], while another investigated several issues at a specific research center, including collaboration, multidisciplinary approaches, support, and dissemination [6]. The remaining six articles primarily discussed the experiences of their respective authors and offered relevant reflections [7-12]. No article in our final sample provided a substantial literature review on the process of building a collaborative research team across different units within the same university department. Based on the evidence from these articles, we identified two main themes, including 1) Building a research network and 2) Networking across university units. An additional literature review conducted by two of the authors, in July 2023, did not result in new publications being included, so this topic does not appear to have had recent international research focus.

Figure 1: Flowchart of the literature review process

Building a Research Network

Organizational factors are essential for building research collaboration. To achieve success, three such factors are particularly important: leadership [5-7,9,12], mentorship [5-7,9,12] and cultural background [12]. In this regard, team leaders should promote team learning, serve as role models, support a favorable climate for cooperation, explain rational decisions, and help team members attain self-efficacy [9]. Thus, skilled team leadership and support are critical provisions for a thriving collaborative research team [6]. In a specific example, Best et al. [5] found that the research community was more likely to remain engaged and informed when the team leader frequently sent informative and humorous emails. A collaborative research team provides a platform of interaction for junior and senior researchers, thus facilitating training and mentorship. In the university context, team membership also helps individual researchers avoid isolation, while providing them with more opportunities to complete their own research [6]. According to Davis et al. [12], various challenges may arise when attempting to build a university-based collaborative research team, especially given the existence of different cultural backgrounds, heterogenous responsibilities, various academic practices, cultural factors, and politics. To establish an excellent, research-intensive environment, teams should help all members discuss their methods and struggles in ways that can unite them toward common goals [6].

Networking Across University Units

A researcher’s ability to network across university units depends on their individual values [7-8,10,12], the time available for research [5-7,12] and computer technology [7]. Meanwhile, an excellent collaborative research team requires focus, flexibility, trust, persistence, and leadership, which are developed through combined personal interests and common purposes. Thus, team success requires mutual respect for individual ideas and contributions as well as transparency during each step of the process [7]. Regarding issues faced by individual researchers, four articles mentioned the challenge of finding time to contribute to research teams [5-7,12], while another noted the constraints associated with simultaneous involvement in several international projects [7]. Under such conditions, it is crucial for both the whole group and individual team members to accept varying degrees of participation at different stages [9]. Based on their experiences in the healthcare field, Best et al. [5] explained how successful research collaboration could increase individual involvement in team aims while facilitating knowledge transfers to students and patients. Three articles emphasized that computer technology is essential for maintaining cooperation across university departments [6-7,9]. In one study, Steinke et al. [7] pointed out that personal computer skills are likely to vary among team members, which may create difficulty. Moreover, the strength and quality of the internet connection may pose challenges in cases where team members need to travel or communicate from different time zones during meetings [7]. Overall, these reports suggest that managers must remain aware of how research collaboration is influenced by personal values, contextual management, mentorship, and the time needed to conduct research. At the same time, the interpersonal elements of the research process depend on mutual trust, focus, and flexibility. In addition to the literature review, we conducted a qualitative study [13] based on a double Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis. Specifically, the SWOT analysis employed a modified standard tool among Norwegian members of a university research team to identify key factors that influenced group performance; these factors were further examined to enhance strengths, optimize opportunities, improve weaknesses, and attenuate threats [14].

Method

Literature Search

We initially gathered evidence on collaborative research team building by searching databases with the assistance of a university librarian, including CINAHL, Medline in PubMed, and PsycInfo. We created search terms using different combinations of the following words: scholarly activities, research, nursing/nursing research, national relation/national cooperation, teamwork, cooperative behavior, and collaboration. For returned articles, we set the following inclusion criteria: peer-reviewed studies with abstracts/full-text articles from 2010 to 2020. These were searched using the Boolean/ phrase technique. We repeated the initial literature search in July 2023 for the time period 2020-2023 and added no new articles to our analysis and findings.

Participants in SWOT Analysis

The SWOT participants included eight members of a university research team established in 2017. Specifically, the team was comprised of four scholars, two lecturers, and two Ph.D. students, with an age range of 35 to 65 years.

Data Collection

We distributed the SWOT template on the first day of a weekly winter summit in 2019, with responses collected shortly after (100% response rate). As the survey took approximately 40 minutes to complete, it is assumed that participants gave their answers spontaneously. We repeated the data collection process on the last day; that is, after the program had ended, but before the evaluation session. Before the distribution of the SWOT template, the participants were informed about the study’s aim, the anonymity of their contribution, and their right to withdraw their written consent anytime. Each participant signed an informed consent form before data collection started. No participant withdrew their participation. In this paper, we have ensured their anonymity by using numerical designations when quoting any statements.

Data Analysis

We analyzed and interpreted the responses from participants with reference to Ricœur’s [13] theory of interpretation. This consisted of a three-level process: a naïve reading, followed by a structural analysis, and concluding with a comprehensive discussion. All authors read and reread the data from the SWOT templates [13], thus identifying a naïve understanding. In the structural analysis, we gathered sections of text (consisting of text portions across the SWOT templates) into larger units of meaning [15]. Finally, we comprehensively discussed the meaning of the text in reference to the selected theory and outcome of the initial literature search.

Results

Naïve Reading

The naïve reading indicated that the participants were responsible, cheerful, and helpful. In general, they enjoyed research collaboration. However, some participants found teamwork burdensome when certain members did not fulfill their obligations. They described new technology as exciting, noting that it streamlined their work. At the same time, good leadership was mentioned as inspiring, while the lack of leadership negatively influenced their ability to work effectively with colleagues. Participants also reported that the process of applying for research funding required too much time when compared to the research outcome, and also affected their ability to attend conferences and meet with the research team.

Structural Analysis

Our structural analysis focused on 311 statements taken from the two surveys (161 and 159 from the first and second rounds, respectively). In both surveys, dominant strengths emerged from statements the participants made about their individual characteristics (35 of 58 and 36 of 50 from the first and second rounds, respectively). On the other hand, weaknesses also emerged. For example, some participants emphasized the challenges of navigating additional tasks (19 of 42 statements from the first round), while others mentioned insufficient knowledge about methodology and scientific factors (14 of 34 statements from the second round). In both rounds, participants highlighted a major opportunity derived from the benefits of being part of a research group (15 of 28 and 19 of 32 from the first and second rounds, respectively). They also identified some threats, including those pertaining to the relationship between their aims and obligations (20 of 33 statements from the first round) and challenges between individuals and their participation in the research team (18 of 34 statements from the second round). Ultimately, we summarized the structural analysis into two themes, including 1) strengths, weaknesses, and threats to building research collaboration and 2) collaborative processes across university units. To keep track of individual statements, we assigned a unique number to each participant (i.e., numbers 1 through 8). Thus, all statements and quotations in the two following subsections are connected to the numbers of relevant participants; to further distinguish between the two rounds of SWOT template completion, we also attached the letter “b” in cases where those statements and quotations were from the second round.

Strengths, Weaknesses, and Threats to Building Research Collaboration

Frequently noted strengths included the ability to work effectively under time pressure (3, 5, 8, 4b, 5b, 6b, 8b) and adopt personal responsibility (2, 4, 7, 8, 2b, 3b, 6b, 8b). One participant stated: “Accountability is an integral part of me as a person” (2). Meanwhile, relevant qualities included courage (2), determination (6, 8, 5b, 8b), curiosity (3, 7, 6b), and commitment (2, 4, 7, 8, 2b, 3b, 4b, 6b). Another strength was the ability to both cope with deadlines and respect the deadlines of others (1, 6, 7). In both surveys, half of the participants said that too many tight deadlines could lead to issues such as pressure (1, 2, 7, 8, 8b) and sleep deprivation (1). Consequently, time pressure was considered a threat to their research activities (1, 1b, 2b, 4, 5, 8, 8b). Some participants wanted their work to be more systematic (2, 7b). For example, one said: “I’m not delivering well under strong pressure; then, I’ll be a little paralyzed” (6b). Only one participant said that she had become better at prioritizing over time (5b). Possessing competence in a specific research method was also considered a strength. In this regard, two participants said that they had extensive research competence (3b, 7b). At the beginning of the seminar, only two participants said that they lacked broad research experience (3, 8); however, four participants mentioned relevant personal weaknesses at the end of the seminar, in terms of either general research competence (3b, 6b, 8b) or a specific lack of expertise linked to quantitative methods (8b) or scientific theories (5b, 8b). Of note, half of the participants identified weaknesses in their own contributions to the research team (4, 5, 6, 8). Some also identified insufficient knowledge about methodology and a lack of fluency in speaking (1) or writing academic English (4, 5, 6, 8). One participant said: “I don’t feel that academic writing comes easy for me” (4). Three participants perceived opportunities regarding new technology, explaining that such provisions could facilitate research collaboration (2, 3, 6, 6b). While one participant said that new technology could enable more efficient work (6b), only one said that technology was an integral part of their field (2).

Collaborative Process Across University Units

As a theme, the collaborative process was focused on interpersonal relationships between participants. For example, they said that they enjoyed collaborating with others (3, 4, 2b, 4b, 8b), and had become more open-minded about each other’s perspectives through teamwork (5). They also perceived themselves as honest (7), loyal (2), and good at listening (5). One participant said that her personal weaknesses were speaking more than listening and losing patience with pessimists (7). Moreover, specific collaboration skills (4, 8, 2b, 6b, 7b, 8b) were considered essential for the development of positive collaborative processes and research networks, particularly including openness to ideas presented by other team members (1, 2, 4, 5b). When describing elements they believed were central to team collaboration, the participants used words and phrases such as encouragement (8), support for progress (8), and the ability to motivate others (6b). Openness to ideas proposed by other people was also a factor that contributed to new perspectives (7b). The participants identified multiple benefits of building research collaboration (1b, 3) and sharing experiences (1b). By jointly collecting data and writing articles, team members developed relationships that helped them enhance their research and produce high-quality publications (8, 8b). They considered research collaboration with both internal and external research partners to be desirable (2b, 8, 7b), noting its contribution to professional development (2, 7b). Other participants said that they received more advice from experienced researchers by building relationships in the research group (3b, 4, 5b), which became an arena for inspiration and support (4b).

Through these relationships, the participants gained access to a “room” where they could be open about their shortcomings and needs (7). There were also threats to building effective collaborative processes, including instances in which others dominated the group (2, 7, 1b, 2b, 4b, 6b, 8b), late (or no) responses from research group members (4, 6, 4b, 7b), the lack of ambition among participants (7, 8), and the absence of mutual trust or respect (5, 4b). Six of the eight participants said that the lack of participation from others was a possible weakness in the collaborative group process (1b, 2b, 3, 3b, 6, 6b, 7, 7b, 8b). For example, one said: “The worst thing when working in a team is when someone says they are going to do something, but they do not do it, or does it badly” (3). Five of the eight participants said that effective team management played a major role in building good collaborative relationships (2, 3, 5, 6, 7, 2b, 8b). As a point of emphasis, leadership was said to motivate and inspire relationships between group members (3, 7). By contrast, individual participants felt discounted when they believed that their leaders did not listen to them (2b, 8b). The ability to establish and maintain local, national, and international networks (7) was considered necessary for group collaboration. Other essential aspects were efforts to include (4) and connect people (2), guide and teach students (7), and teach others how to perform. For example, a phenomenological analysis was mentioned (1). One participant said that it was essential to become involved in research conducted by other members (7b).

Discussion

This study critically reviewed the recent literature on building research collaboration, then compared this evidence with the collaborative process experienced by a publicly funded healthcare research team that spanned multiple university units, as collected via a SWOT analysis. The literature review revealed two main themes:

  1. building a research network and 2) networking across university units. The structured SWOT analysis also identified two themes:
  2. strengths and threats in building research collaboration and
  3. collaborative processes across university units (Table 1). In the following subsections, we incorporate a theoretical perspective to provide a comprehensive discussion that is relevant to our study aim.

Table 1: Themes identified from the literature review and local SWOT analysis

ThemeFrom: Literature reviewFrom: Local SWOT analysis
1Building research networkStrengths and threats to building research teamwork
2Networking across university unitsCollaborative processes across university units
 

Building Research Networks

Evidence from the eight reviewed articles indicated that organizational factors could form barriers to research collaboration in the context of publicly funded specialized healthcare research teams. The SWOT participants mentioned similar issues. For example, their faculty leadership did not understand that tight time schedules influenced their ability to conduct research. As a specific hindrance, time pressure threatened their research activities because it reduced opportunities for sleep. In a previous study, Maslach and Leiter [16] found that burnout was more likely to occur when organizational demands exceeded individual capacities. Although work management abilities vary between researchers, they are still affected by relationships between the researcher, group leader, and faculty leadership [17]. Here, leadership styles matter. Autocratic leaders simply dictate group activities and work tasks [18], thus deciding how much group members should contribute without asking for their input [18]. This diminishes agency within the team, which can be solved through a more democratic leadership style that allows collaborative decision-making [18]. Our data analysis also showed that autocratic management styles could threaten research collaboration, especially when leaders demanded rapid solutions, as this further tightened the time schedule. In the literature review, four articles reported that insufficient financial support was a potential barrier [5,7,9,10]. The same problem was mentioned by three of the SWOT participants. Without funding, it can be much more difficult for researchers to test their ideas [19]. This also creates publication hardship. For example, Malhotra [20] found that most academicians in India faced considerable expenses when attempting to gain journal publication, especially in periodicals with high impact factors. However, our SWOT participants did not mention this barrier, perhaps because public universities in Norway offer publication funding.

Networking Across University Units

The SWOT analysis revealed that personal values, transformational leadership, mentorship, and access to financial resources could influence research network collaboration across university units. Interpersonal elements of the research process were also important, including mutual trust, consistent focus, flexibility, and the ability to find time for group collaboration. Previous research has also shown that collaboration groups can more easily work toward common goals when they are situated in excellent research-intensive environments (6). However, the ability to work effectively under time pressure varied considerably among our SWOT participants. Some expressed feelings of stress when navigating multiple tight deadlines, while others reported improved prioritization ability with increased experience. Mentorship can prevent burnout by helping inexperienced researchers learn how to balance different work tasks [6] and develop new skills [21]. This makes provision of mentorship especially important for young academicians. For nursing scholars, mentorship can encourage positive relational, attitudinal, behavioral, career, and motivational changes [22]. Our SWOT participants mentioned some additional barriers to research collaboration, including limited research experience and difficulties with academic English.

Of note was that four participants emphasized that their weaknesses in both research experience and academic English skills hampered their contributions to the research group, neither of which factors clearly emerged through our literature review. Nevertheless, Dorsey et al. [9] and Cohen et al. [6] said that collaborative group leaders and experienced researchers should jointly serve as role models. Functioning in such a capacity entails facilitating interactions with junior researchers, who can therefore benefit from better training and mentorship for life in academia. Differences in computer skills and internet access can affect availability, thus impacting the degree to which team members can collaborate [7]. As such, researchers should develop and employ technology to improve communication between team members who are geographically distant (Dorsey et al.[9]; Cohen et al. [6]. Moreover, collaborative groups can contact their university’s information/computer technology departments to ensure that necessary computer and web technologies are available [9]. Finally, Steinke et al. [7] recommended a backup plan if videoconferencing fails, including email correspondence or other free internet software applications. In the modern technological environment, numerous tools support collaboration and the development of professional skills in the university setting [23]. In fact, none of our SWOT participants mentioned computer technology as a barrier to the research process or group collaboration, suggesting that they worked in a technology- rich environment. At the same time, personal computers have become increasingly common in research environments.

Motivation is also essential for international collaboration [24]. In this regard, Bass et al. [25] argued that inspirational leadership with a motivational focus on personal behavior could provide meaning while challenging team members to efficiently achieve future goals. According to Anselmann and Mulder [26], transformational leadership can further help leaders identify potential areas of change and encourage necessary adjustments. However, an open-minded view of other perspectives can be interpreted as a wish to view collaborating partners as equals, which may be challenging when team members possess different skills and experiences [27]. According to our findings, mentorship can reduce problems related to time pressure and the lack of academic skills. This is greatly beneficial for inexperienced researchers, who can realize personal development, increased research productivity, and better career opportunities [28]. As a practical example, our SWOT participants expressed the desire to develop skills in writing applications under the guidance of senior members. Based on our experiences in this study, we envision opportunities for research group leaders to employ SWOT templates. Such an approach will clarify team strengths and weaknesses, which can help them customize their mentorship accordingly.

Study Strengths and Limitations

As regards strengths, this study conducted a preliminary comprehensive literature review, which became a benchmark when discussing our analysis and findings. However, there were also some limitations. First, the participants were exclusively invited to participate in the research seminar, and may have therefore been more positive and open toward both their own development and SWOT factors in general. However, the group was also comprised of novice and expert researchers, who addressed a situation that similar research teams may experience, which constitutes a strength. Second, the participants were required to complete the SWOT template within a limited time, which may have elicited superficial answers to the four explored areas. However, they were also able to build on their initial answers during the second survey round, which thus constitutes a strength in data collection, as evident in the enhanced development of their responses.

Conclusion

This study found that supportive leadership and active mentorship between experienced and inexperienced team members could facilitate the research process and increase collaboration in the context of a publicly funded specialized healthcare research team. Of note, supportive leadership is highly essential. Our SWOT participants said that their ability to motivate and support other team members depended on whether the team leader offered the same provisions. Our perception is that supportive and motivated team leaders can serve as positive role models for the entire team, thus creating a group culture that prevents non-participation or late responses from members. In most scientific endeavors, the establishment and maintenance of a collaborative research team are fundamental to success.

Implications for Nursing

  • Supportive leadership is highly essential for nurse researchers to flourish.
  • Nurse managers may not have research experience or necessary insight into the working conditions that support research collaboration
  • It is important to adopt a transformational leadership style in which a dialogical practice can support specialized healthcare research teams in their positions.

Conflicting Interest

None.

Disclosure

The authors report no conflicts of interest in this work.

Funding

We thank Nord University for funding a Winter Summit in 2019 and providing a grant for Mrs. Hansen to act as a research assistant for professor Uhrenfeldt in 2019-20.

Ethical Approval

No ethical approval was required for this research. The study is registered at Nord University (FSH by j.no 24.04.20).

Author Contributions

Study design: LU. Data collection (Literature search); quality appraisal and data analysis: MCH, LU, KI. Data collection (SWOT analysis): MCH supervised by LU. Manuscript preparation MCH, supervision, and critical review by LU, KI. All authors critically reviewed and approved the final manuscript.

Language Editing

This paper is edited by The Golden Pen.

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Perception and Attitude of the General Population of Zanjan, Iran in Comparison to Medical Students Toward Schizophrenia

DOI: 10.31038/IJNM.2024543

Abstract

Background: The perception and attitude of the general population and health-care workers towards psychiatric disorders have a direct effect on the outcome of these diseases. Negative perceptions and attitudes can lead to worse social facilities (such as employment, and housing), lower self-esteem, help-seeking behavior, as well as complications in receiving health care. Little information is available about the perception and attitude towards schizophrenia in Iran.

Methods: This study was conducted to evaluate the perception and attitude of the general population and medical students toward schizophrenia in Zanjan province, Iran. Several possible factors affecting perception and attitude were also evaluated. A descriptive-analytical cross-sectional study was conducted on 788 medical students and the general population of Zanjan province. A researcher-made questionnaire was used to collect data.

Results: The scores of perception and attitude toward schizophrenia were compared between the two populations. In the comparison of the two general and medical populations, only a significant relationship was found between the attitude of ineffectiveness (significance = 0.001) and stigmatization attitude (significance=0.001), which means that the attitude of the general population is more negative than the medical population.

Conclusion: No correlation was found between gender and level of education with attitude and perception towards schizophrenia. A statistically significant relationship was found between family history and negative attitude towards schizophrenia. A significant relationship was also found between taking a psychology or psychiatry course with a more positive attitude and perception towards schizophrenia.

Keywords

Schizophrenia, Perception, Attitude, Iran

Introduction

Schizophrenia is a mental illness with features such as delusions, hallucinations, disturbed behavior, and negative symptoms that impairs social and occupational functioning and is quite debilitating [1]. According to the World Health Organization’s definition, schizophrenia is a severe disorder that usually begins in late adolescence and early adulthood [2]. A key feature is disordered thinking and perception, often accompanied by inappropriate emotions. The lifetime prevalence of schizophrenia in the United States is around one percent [3]. The prevalence of psychosis especially schizophrenia in Iran is the same as in other countries and is estimated to be around one percent of the general population [4]. Perception and attitude have different definitions in various fields of psychiatry, psychology, and sociology. Social perception refers to how a person is seen by society or other people [5]. Attitude is a state of mental readiness that is acquired through experience and has a direct and dynamic impact on an individual’s response to all attitude-related issues and situations [6]. Perceptions and attitudes toward mental disorders may be positive or negative. Social stigma refers to the negative beliefs and attitudes of the general population towards individuals with mental disorders [7]. A common belief is that people with schizophrenia are unpredictable, dangerous, aggressive, and inadequate. Therefore, many people may have a strong tendency to maintain social distance from these people [8]. Social stigma, apart from the mental illness itself, has serious negative consequences for individuals with mental disorders. It can lead to damaged social facilities (such as employment and housing), lower self-esteem, help-seeking behavior, ruined friendships, and familial relationships, as well as complications in receiving health care. Mental illness stigma can also lead to delays in receiving treatment [9]. In Iran, research has been conducted on stigma towards mental disorders. The global nature of stigma, lack of awareness among mental health professionals and other experts, cultural barriers, policy-making structures, and lack of financial resources are all obstacles to improving stigma [10]. In studies conducted within Iran, even medical students who undergo clinical training may have negative attitudes toward mental disorders [11]. There is limited information about the perception and attitude toward schizophrenia in Iran. Therefore, this study was conducted to evaluate the perception and attitude of residents of Zanjan province and medical students in this province towards schizophrenia.

Methods

Study Type and Population

This study is a descriptive-analytical cross-sectional study conducted in 2023-2024 on two groups of medical students and the general population of Zanjan province. All medical students who were studying at Zanjan University of Medical Sciences in 2023 were used as the source population for the “medical” group. Patients referred to Ayatollah Mousavi Hospital’s clinics were also used as the source population for the “general population” group. The inclusion criteria for the study were medical students at Zanjan University of Medical Sciences or visitors to the Ayatollah Mousavi clinic in Zanjan in 2023 who were able to read and write, willingness to participate in the study, ages between 18 and 70 years old, and negative history of psychiatric illness. The exclusion criteria were illiteracy, unwillingness to participate in the study, ages over 70 or under 18 years old, and a positive history of psychiatric illness in the participant.

Sample Size

Based on similar studies, the G*power software was used to estimate sample size by comparing the means of two independent groups. Since the means of the two groups were estimated to be close to each other, a smaller effect size (0.2) was chosen to obtain a larger sample size. A type alpha error probability of 0.05 was considered. The sample size for the “medical” group was estimated to be 394. The sample size for the “general population” group was also estimated to be 394 and convenience sampling was used to select the general population from visitors of the clinics.

Data Collection Tool, Validity, and Reliability of the Questionnaire

A researcher-made questionnaire was used to evaluate the attitude and perception towards schizophrenia. This questionnaire consisted of 23 questions that were extracted from similar studies [12-30]. The questions were adjusted based on Iranian culture and social conditions. For example, in studies conducted in African countries, factors such as witchcraft, evil eye, and god’s will were identified as causes of schizophrenia [14], but such cases were not included in the researcher-made questionnaire. Instead, factors such as stress, physical and chemical brain disorders, poverty, etc., which are more compatible with the cultural conditions of Iran, were included as possible etiologies of schizophrenia [21]. A three-point Likert scale (1-3) was used to score the questions in the questionnaire. A score of 1=agree, 2=not sure, and 3=disagree was considered, with a lower score indicating a more positive attitude and perception. Demographic factors such as gender, age, and education level were also asked of the participants. A family history of psychiatric disorders was also asked of the participants. Participants were also required to indicate if they had completed a psychology or psychiatry course before. The content validity of the questionnaire was evaluated by psychiatry and Persian literature professors, and corrections were made before sampling. Cronbach’s alpha test was used to assess the reliability of the questionnaire. The internal consistency analysis of the 23-item schizophrenia scale yielded a Cronbach’s alpha of 0.55, which increased to 0.68 after removing items 7-8-9-10-15-16-20-22.

A psychiatrist developed case vignette was used to help the general population what was meant by schizophrenic people.

Variables

The dependent variables include perception and attitude toward schizophrenia. Independent variables include demographic characteristics, family history of psychiatric disorders, and completion of a psychology or psychiatry course.

Data Analysis Method

Incomplete questionnaires were excluded from the study. The data were entered into SPSS version 26 software. The frequency distribution of demographic variables was examined. The frequency distribution of responses to schizophrenia questionnaire items was also examined individually. The reliability of the questionnaire was evaluated using Cronbach’s alpha, which reached 0.68 after removing some items. The remaining items were subjected to exploratory factor analysis with varimax rotation. These items were divided into four factors: perception of the etiology of schizophrenia, attitude toward the inefficacy of schizophrenia, attitude toward the stigmatization of schizophrenia, and attitude toward the destigmatization of schizophrenia. Perception and attitude scores regarding schizophrenia were compared between the two general and medical populations using the t-test. The relationship between completion of a psychology or psychiatry course, family history of psychiatric disorders, gender, education level, and age with perceptions and attitudes toward schizophrenia was also examined using an independent t-test. Finally, independent variables with a significance level less than 0.05 were considered statistically significant.

Results

Demographic Characteristics

A total of 394 medical students and 394 individuals from the general population were included in the study. 99.2% of the medical students were between the ages of 18 and 30 and the number of medical students over the age of 41 was zero. 57.9% of the general population were between the ages of 18 and 30. 43.4% of the participants in the medical group were male and 56.6% were female. In the general group, 53% were male and 47% were female. Almost half the general population has a university education and half does not (Table 1).

Table 1: Socio-Demographic Characteristics of Respondents

Variable

  Frequency

Percentage (%)

Age groups  

18-30 y/o

31-40 y/o

41-50 y/o

51-60 y/o

61-70 y/o

General population

228

80

47

31

8

Medical population

391

3

0

0

0

General population

57.9%

20.3%

11.9%

7.9%

2%

Medical population

99.2%

0.8%

Gender Male

Female

209

185

171

223

53%

47%

43.4%

56.6%

Educational level Non-university Graduates

University Graduates

Medical students

199

195

394

50.5%

49.5%

 

50%

Factor Analysis

Internal consistency of the 23-item schizophrenia scale through Cronbach’s alpha yielded a value of 0.55, which increased to 0.68 after removing items 7-8-9-10-15-16-20-22. The remaining 15 items were subjected to factor analysis with varimax rotation.

Factor one, which makes up 25.69% of the variance includes six questions that are all about the etiology of schizophrenia. This factor was named perception of the etiology of schizophrenia.

Factor two, which makes up 17.74% of the variance includes three questions that are all about the capacity of an individual in their personal and work relationships. This factor was named the attitude of the inefficacy of schizophrenia. Factor three, which makes up 11.01% of the variance includes two questions that are both about destigmatization. This factor was named the attitude of destigmatization of schizophrenia. The scores for this factor were reversed meaning a score of one meant disagree and a score of three meant agree. Factor four, which makes up 7.91% of the variance includes four questions that are all about stigmatizing. This factor was named the attitude of stigmatization of schizophrenia.

As seen in Table 2, item 23 (schizophrenia can be transmitted to others) has a negative loading on Factor 1 and requires reverse scoring in the analysis (Table 3).

Table 2: Component matrix

 

Component

1 2 3

4

17-Physical and chemical disorders in the brain are one of the possible causes of schizophrenia

0.84

     
1-Accidents or traumatic events are factors that cause or aggravate schizophrenia

0.82

     
2-Drug and alcohol misuse are factors that cause or aggravate schizophrenia

0.82

     
3-Schizophrenia is hereditary

0.81

     
4-Poverty is a factor that causes or aggravates schizophrenia

0.74

     
5-Stress is a factor that causes or aggravates schizophrenia

0.73

     
13-People with schizophrenia should be allowed to make decisions in their family  

0.94

   
14-It’s possible to establish a friendship with someone who has schizophrenia  

0.93

   
21-A person who has schizophrenia could have a favorable career path  

0.92

   
19-Those who have schizophrenia should be confined in care centers    

0.90

 
18-The main culprit in causing schizophrenia is the person himself    

0.89

 
11-It’s not necessary for people with schizophrenia to be admitted to medical centers      

0.67

6-A person with schizophrenia can live in society with others if they receive proper treatment      

0.57

23-Schizophrenia could be transmitted to others      

-0.52

12-A person with schizophrenia can get married and start a family      

0.38

Table 3: Perception and attitude toward schizophrenia among medical and general population.

   

 

  Leven’s test T-test  
Frequency Mean Standard deviation F Significance t df Sig. (2-tailed) Mean difference

D cohen

Perception of etiology General

394

9 2.98 0.77 0.37 3.37 786 0.001 0.697 2.89

Medical

394 8.30

2.80

Attitude of inefficacy General

394

5.85 2.12 4.57 0.03 5.41 786 0.001 0.835 2.16
Medical 394 5.01

2.20

Attitude of destigmatization General

394

2.72 1.12 0.41 0.52 1.71 786 0.086 0.144 1.81

Medical

394 2.87

1.23

Attitude of stigmatization General

394

8.33 1.35 12.87 0.001 6.78 786 0.001 0.558 1.49

Medical

394 7.61

1.49

Comparison of Perception and Attitude Scores Regarding Schizophrenia in the General and Medical Populations

In the comparison of the scores of perception and attitude towards schizophrenia in both general and medical populations, the variables attitude of inefficacy of schizophrenia (significance = 0.03) and attitude of stigmatization of schizophrenia (significance = 0.001) are significant. Since the lower the mean, the more positive the attitude is, the attitude of the general population (mean = 5.85) in ineffectiveness is more negative than the medical population (mean = 5.01). The attitude of the general population (mean = 8.33) in stigmatizing schizophrenia is more negative than the medical population (mean = 7.61).

Association Between Taking a Psychology or Psychiatry Course with Perception and Attitude Toward Schizophrenia

417 out of 788 participants have completed a psychology or psychiatry course unit. This means that 53% of the population has been trained in the field of psychiatric disorders and 47% has not been trained. The two groups have a significant difference in all variables except for the variable of destigmatization of schizophrenia (significance = 0.07), which means that people who have passed a psychology or psychiatry course (mean = 8.37) have a more positive perception than those who have not received psychiatric training (mean = 8.96). Also, those who passed a psychiatry course have a more positive attitude of inefficacy and stigmatization (mean = 5.10 and 7.67) than those who did not pass such a course (mean = 5.80 and 8.32) (Table 4).

Table 4: Taking a psychiatry or psychology course and its association with perception and attitude toward schizophrenia.

 

T-test

     
t df Sig. (2-tailed) Has taken a psych course Frequency

Mean

Perception of etiology

-2.86

773.27 0.004 Yes 417 8.37
No 371

8.96

Attitude of inefficacy

-4.54

775.36 0.001 Yes 417 5.10
No 371

5.80

Attitude of destigmatization

1.76

785.99 0.07 Yes 417 2.87
No 371

2.72

Attitude of stigmatization

-6.12

784.36 0.001 Yes 417 7.67
No 371

8.32

Association Between Family History of Psychiatric Disorders and Perception and Attitude Toward Schizophrenia

Only in the stigmatizing attitude of schizophrenia, there is a significant difference between those who have a family history of psychiatric disorders and those who do not (significance = 0.008). Those who have a family history (mean = 8.16) show a more negative attitude towards stigmatization than those who do not have a family history (mean = 7.86) (Table 5).

Table 5: Family history of psychiatric disorders and its association with perception and attitude toward schizophrenia.

 

T-test

     

t

df Sig. (2-tailed) Family history of psychiatric disorders Mean

Standard deviation

Perception of etiology

-0.72

784 0.46 Yes 8.55 2.87
No 8.71

2.94

Attitude of inefficacy

-1.25

784 0.20 Yes 5.29 2.24
No 5.50

2.17

Attitude of destigmatization

1.18

784 0.23 Yes 2.86 1.26
No 2.76

1.13

Attitude of stigmatization

2.66

784 0.008 Yes 8.16 1.52
No 7.86

1.53

Association Between the Level of Education of the General Population and the Perception and Attitude Towards Schizophrenia

There is no significant difference in the attitude and perception of schizophrenia between university graduates and non-university graduates in the general population (significance>0.05) (Table 6).

Table 6: Educational level of general population and its association with perception and attitude toward schizophrenia.

 

T-test

     
t df Sig. (2-tailed) Educational level Mean

Standard deviation

Perception of etiology

-0.86

392 0.39

University

8.87 2.90

Non-University

9.13

3.07

Attitude of inefficacy

0.27

392 0.78

University

5.87 2.15

Non-University

5.82

2.10

Attitude of destigmatization

0.71

392 0.47

University

2.76 1.13

Non-University

2.68

1.12

Attitude of stigmatization

-0.75

392

0.45

University

8.28

1.37

Non-University

8.38

1.34

Association Between Gender and Perception and Attitude Towards Schizophrenia

There is no significant difference in the attitude and perception of schizophrenia between males and females in the general and medical population (significance>0.05) (Table 7).

Table 7: Gender and its association with perception and attitude toward schizophrenia.

 

T-test

     
t df Sig. (2-tailed) Gender Frequency

Mean

Perception of etiology

0.72

786

0.46

Male

380

8.73

Female

408

8.58

Attitude of inefficacy

0.27

786

0.78

Male

380

5.45

Female

408

5.41

Attitude of destigmatization

0.58

786

0.55

Male

380

2.82

Female

408

2.77

Attitude of stigmatization

-0.10

786

0.91

Male

380

7.97

Female

408

7.98

Association Between Age and Perception and Attitude Towards Schizophrenia

Due to the heterogeneity of the sample of the medical population, it was not possible to compare the two populations in terms of age. Also, because the number of medical students from the age group of 41 and above becomes zero, it is not possible to compare age groups with each other (Table 8).

Table 8: Responses to the items of the perception and attitude toward schizophrenia questionnaire.

 

 

  Medical population     General population  
  Items Agree Neutral Disagree Agree Neutral

Disagree

1 Accidents or traumatic events are factors that cause or aggravate schizophrenia

67.3%

27.7% 5.1% 57.6% 34.8%

7.6%

2 Drug and alcohol misuse are factors that cause or aggravate schizophrenia

66.8%

28.2% 5.1% 62.7% 29.4%

7.9%

3 Schizophrenia is hereditary

65.2%

28.4% 6.3% 61.7% 31.7%

6.6%

4 Poverty is a factor that causes or aggravates schizophrenia

64.7%

31.2% 4.1% 47.7% 44.4%

7.9%

5 Stress is a factor that causes or aggravates schizophrenia

66.8%

28.2% 5.1% 56.9% 35.3%

7.9%

6 A person with schizophrenia can live in society with others if they receive proper treatment

27.4%

26.1% 46.4% 18.8% 29.4%

51.8%

7 A person with schizophrenia is violent and dangerous

30.5%

32.2% 37.3% 24.9% 29.9%

45.2%

8 A person with schizophrenia can be treated with medicine

18%

61.2% 20.8% 17.8% 60.7%

21.6%

9 Anyone may get schizophrenia in their lifetime

13.5%

29.4% 57.1% 16% 25.9%

58.1%

10 A person with schizophrenia has mental retardation

14%

26.9% 59.1% 13.7% 23.6%

62.7%

11 It’s not necessary for people with schizophrenia to be admitted to medical centers

20.1%

26.1% 53.8% 9.1% 12.4%

78.4%

12 A person with schizophrenia can get married and start a family

35.5%

41.9% 22.6% 17.3% 64%

18.8%

13 People with schizophrenia should be allowed to make decisions in their family

50.5%

31.2% 18.3% 30.5% 43.4%

26.1%

14 It’s possible to establish a friendship with someone who has schizophrenia

51.5%

29.7% 18.8% 38.1% 38.6%

23.4%

15 Lack of social support may cause or aggravate schizophrenia

78.9%

11.7% 9.4% 86.5% 8.6%

4.8%

16 If diagnosed early, schizophrenia is treatable

55.1%

21.3%

23.6% 60.9% 22.6%

16.5%

17 Physical and chemical disorders in the brain are one of the possible causes of schizophrenia

69.5%

25.4% 5.1% 58.1% 34.8%

7.1%

18 The main culprit in causing schizophrenia is the person himself

11.4%

19.5% 69% 8.9% 18.8%

72.3%

19 Those who have schizophrenia should be confined in care centers

10.2%

24.6% 65.2% 6.3% 23.6%

70.1%

20 A person with schizophrenia should have the same human rights as others

68.5%

18.5% 12.9% 80.5% 9.9%

9.6%

21 A person who has schizophrenia could have a favorable career path

51.3%

31% 17.7% 31% 34%

35%

22 Lack of awareness and insight in a schizophrenic patient causes ineffective treatment

70.3%

16.8% 12.9% 77.6% 13.5%

8.9%

23 Schizophrenia could be transmitted to others

4.3%

13.2% 82.5% 4.6% 20.8%

74.6%

Discussion

The present study was conducted to investigate the perception and attitude toward schizophrenia in both the general population and medical students in 2023. In this research, no significant relationship was found between gender and perception and attitude towards schizophrenia, these results are in line with the study conducted in Oman [31]. According to the findings, a significant relationship was found between the family history of psychiatric disorders and the attitude towards schizophrenia, that is, those who have a positive family history show a more negative attitude. Meanwhile, in the studies of Lebanon and Ethiopia, people who knew a person with mental illness among their acquaintances and family had a more positive attitude towards these patients [13,25]. At the same time, in the Baghdad research, no relationship was found between a positive family history and attitude toward mental disorders [26], this difference in results is justifiable. Since a precise and uniform definition of attitude and perception is not provided in different sources, sometimes the measured factor shows the respondent’s knowledge rather than the attitude and perception. Such questions are also seen in some of the mentioned studies and these questions may have measured the level of knowledge of the person. In this case, it is natural that if you have a positive family history of psychiatric disorders, the level of knowledge about these diseases will be higher than the rest of the people. Cultural and social differences in societies are another reason. In Western societies where there is more social support for these patients, treatments are more available and education about psychiatric disorders starts from a young age, it is natural that the attitude towards these patients is not so negative. However, in Iranian society, where education about psychiatric disorders is not provided, the government does not support such patients, and the high cost of treatment can lead to a more negative attitude towards psychiatric disorders. Sometimes people with stigma and negative attitudes towards these disorders wish to consider themselves exempt from these disorders. However, it seems that the results obtained in Iran are in line with the results seen in practice.

In our study, there was no statistically significant relationship between the level of education and the perception and attitude toward schizophrenia, which is in line with the studies of Oman and Baghdad [26,31]. At the same time, in the Ethiopian study, illiterate people or people who had non-university education showed a more positive attitude towards schizophrenia [14]. In the study of Lebanon, stigma is lower in women, young people, and university graduates than in other groups [25]. In our study, a relationship was found between having taken a psychology or psychiatry course with perception and attitude toward schizophrenia. This means that those who have completed psychology or psychiatry courses show a more positive attitude and perception. These results are in line with the Moroccan study [29]. In our study, a significant relationship was found in the attitude towards schizophrenia in the comparison of two general and medical populations, which means that the general population showed a more negative attitude than medical students. These results are in line with Amini’s study in Iran [30]. In our study, the general population recognized the lack of appropriate social support, drug and alcohol use, and genetics as the main causes of schizophrenia, which is in line with the results of studies in Ethiopia and Saudi Arabia [13,14,24]. Meanwhile, the medical community recognized the lack of appropriate social support, physical and chemical disorders in the brain, and stress as the main causes of schizophrenia, which is closer to the studies of Ghana and China [20,21].

According to the findings, almost half of the general population believes that schizophrenic patients are not dangerous and violent, which is in line with the study of Saudi Arabia [24], but not in line with the research of Ethiopia [13,14]. In our research, almost three-quarters of the general population and half of the medical population believe that it is necessary to admit schizophrenic patients to medical centers, which is closer to the Indian study [32]. Meanwhile, in the Ethiopian study, only 39.4% of the participants have the same belief [14]. At the same time, in the study of Ghana, 90% of the participants believed that schizophrenic patients should be hospitalized in treatment centers [20]. In our study, 80% of the general population agreed with the equality of human and social rights of people with schizophrenia with the rest of the population, which is not in line with the Ethiopian research [13]. Meanwhile, only 30% believed that these patients could have a favorable career future, which is in line with the studies of India and Saudi Arabia [24,33]. In our study, about 20% of the general population believed that schizophrenic patients can get married, and the same percentage believed that it is impossible to establish a friendship with schizophrenic patients. These results are in line with the study of Ghana and Canada [15,20], but not in line with the studies of southern Ghana and Saudi Arabia [24,34].

About 60% of the general population disagrees that schizophrenic patients have some kind of mental retardation, which is not in line with the study in Ghana [20]. This difference in results can be explained by the cultural differences and the level of education about psychiatric disorders in different societies. Only 16% of the general population believe that anyone may suffer from schizophrenia during their lifetime, which is much lower than studies in Ghana, Saudi Arabia, and southern Ghana [20,24,34]. One of the reasons for the difference in the results could be that by answering this question negatively, people want to rid themselves of this disease. Knowledge of the prevalence of schizophrenia in the general population can also be another influential factor. Since the prevalence of this disease in society is not very high, its estimation by the general population is not high either.

Conclusion

The results of this study showed that there is no significant relationship between gender and education level with perception and attitude toward schizophrenia. Those who have a family history of psychiatric disorders show a more negative attitude towards schizophrenia. A significant relationship between taking a psychology or psychiatry course with positive perception and attitude toward schizophrenia was also found. The general population has a more negative attitude towards schizophrenia than medical students. Lack of proper social support was recognized as the most common cause of schizophrenia.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Funding Statement

No financial support was received from any organization or persons.

Acknowledgments

We would like to extend our gratitude to Zanjan University of Medical Sciences for providing the opportunity to conduct the study and issuing the code of ethics.

Ethical Considerations

Zanjan University of Medical Sciences ethics committee provided the ethics code (IR.ZUMS.REC.1402.146) for this project.

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Examining the Effectiveness and Implementation of Patient Fertility Decision-Aid Tools for Cancer Patients: A Systematic Review

DOI: 10.31038/IJNM.2024542

Abstract

Objective: This study aims to comprehensively understand the actual application of fertility decision support tools in the cancer patient population and their impact on reproductive outcomes. By introducing eight assessment concepts, including acceptability, adoption, appropriateness, feasibility, fidelity, cost, penetration, and sustainability, the tool is comprehensively evaluated. Ultimately, this study aims to provide more comprehensive fertility decision support for cancer patients, offering valuable insights for future research and clinical practice in this domain.

Methods: In August 2023, a comprehensive search was conducted across a total of 14 databases, including MEDLINE, CINAHL, PubMed, PsycINFO, Embase, Scopus, Web of Science, AMED, Cochrane, Google Scholar, CNKI, WanFang Data, VIP, and Sinomed. The included literature underwent methodological quality and bias risk assessment using a mixed-methods appraisal tool.

Results: A total of 11 studies were included for analysis, comprising 5 randomized controlled trials (RCTs), 3 non-randomized controlled studies (N-RCTs), 2 mixed-methods studies, and 1 quantitative cross-sectional study. The findings indicate that research on fertility decision support tools primarily focused on aspects such as fertility-related knowledge, decisional conflict, post-decision regret, satisfaction with information acquisition, the patient’s willingness for reproduction, and the characteristics of the decision support tool. Newly identified themes encompassed decision preparedness, family involvement, informed consent, social support, health literacy, and quality of life. Among the 11 studies included, there was a greater emphasis on the aspects of acceptability, adoption, appropriateness, and feasibility. Other aspects received no attention, including fidelity, cost, penetration, and sustainability.

Conclusion: This study delves into the potential impacts on reproductive outcomes when cancer patients utilize fertility decision-support tools. Through a systematic literature review, new fertility-related themes were identified under the umbrella of fertility decision support tools. However, further research is warranted to comprehensively assess the clinical application of these tools, thereby elucidating their advantages and ultimately enhancing the quality of decision-making for patients facing fertility-related issues.

Keywords

Cancer, Fertility, Decision support, Fertility preservation, Fertility decision-aid tools, Clinical application, Systematic review

Introduction

Fertility is crucial for the continuation of human life, and early adulthood is traditionally regarded as the prime time for individuals to have their own biological children. However, among cancer survivors, reproductive function is often compromised or interrupted due to the destructive nature of cancer itself or the reproductive toxic effects of cancer treatments, particularly in adolescents and young adults (15-39 years old) [1]. With the continuous advancement of comprehensive treatments such as surgery, chemotherapy, radiation therapy, and hormonal therapy, the survival rates of young patients have significantly improved. However, these treatments have both short-term and long-term adverse effects on patients’ fertility, especially in terms of ovarian damage [2]. Studies have shown that, compared to the general population, this gonadal injury may lead to a higher incidence of premature ovarian insufficiency and azoospermia, resulting in early menopause or infertility [3]. With the steady improvement of five-year survival rates among cancer patients [4], over 85% of adolescent and young adult (AYA) cancer survivors express a strong desire for fertility and aspire to become biological parents [5]. Following treatment completion, fertility becomes a focal point of concern for patients, their families, and healthcare providers [6-9]. A comprehensive systematic review concluded that the majority (66%-100%) of cancer patients express a desire to understand the impact of treatment on their fertility [10]. Among young patients without children or with plans for future parenthood, this need and emphasis are even more pronounced, with the proportion of patients seeking relevant information ranging from 0% to 85% [11]. Many guidelines have provided recommendations regarding fertility concerns in patients. International guidelines emphasize that oncologists should inform patients about the potential for treatment-induced infertility and, when necessary, refer them to reproductive medicine specialists before formulating a cancer treatment plan [12]. Clinical practice guidelines from the American Society of Clinical Oncology suggest that healthcare professionals should engage in early discussions with female cancer patients who wish to preserve fertility before treatment in order to offer them more options [13]. Despite an increase in the proportion of fertility counseling initiated by oncologists, less than half of cancer patients are satisfied with the fertility counseling they receive, and the rate of referrals to fertility specialists remains low [14,15]. When receiving reproductive counseling, most patients express an urgent need for more timely, standardized, and written information to address their unmet specific informational needs [16]. However, approximately half of patients (43%-62%) still perceive the information they receive as inadequate and insufficient to meet their needs [17]. A cross-sectional study indicated that less than 10% of adolescent and young adult (AYA) cancer patients received fertility preservation services [18]. In clinical practice, cancer patients face numerous factors that influence their fertility choices. Firstly, they may lack sufficient fertility knowledge [19,20], and their awareness of fertility preservation methods may also be relatively low [21]. Furthermore, there is a severe deficiency in supportive information services related to fertility [22], compounded by the complexity of available fertility preservation options [23], making patients consider many intricate factors in their decision-making. Consequently, the choice of treatment regimen and timing limitations [24], as well as communication issues between patients and healthcare professionals [25], add to the decision-making challenges. Additionally, a range of ethical, legal, and ethical issues need to be considered [26-28]. It should be noted that not all fertility preservation options are suitable for every patient. Depending on factors such as the patient’s age, family status, cancer type, treatment modality, prognosis, and the timing before treatment initiation, some options may be more suitable than others when it comes to preserving fertility. Hence, patients face significant stress and conflicts in making fertility decisions. If patients do not receive comprehensive information about all fertility preservation options or lack support during the decision-making process, the difficulties in decision-making are exacerbated [17,29,30]. Simultaneously, oncology healthcare providers have also reported insufficient knowledge about fertility preservation methods and establishing connections [31,32]. To address these issues, decision support interventions have been developed for both patients and healthcare providers [33,34], aiming to enhance understanding of fertility preservation methods and reduce conflicts in the decision-making process for cancer patients [35].

Decision Aid Tools (PtDAs) are evidence-based tools that assist users in making preference-sensitive decisions by providing information specific to a particular health condition. They emphasize the benefits, risks, probabilities, and uncertainties associated with different choices related to a health condition, allowing patients to clarify their values and consider each option according to their personal preferences before making an informed decision [36]. To address decision-making regarding fertility preservation in female cancer patients, relevant guidelines recommend that healthcare professionals offer decision aids to women considering fertility preservation [12]. Numerous PtDAs for fertility preservation have been developed, and they have demonstrated positive initial application outcomes. These tools significantly enhance patients’ understanding of fertility preservation, reduce decisional conflict, and achieve high overall patient satisfaction. Over 115 randomized controlled trials have indicated that patient decision aids improve decisional conflict by increasing knowledge, fostering realistic expectations, building self-efficacy, and enhancing decision involvement [37]. A previous systematic review has indicated that patient decision aid tools (PtDAs) may play a crucial role in providing information and guiding decisions in this context. Wang et al. (2018) [35] conducted a systematic literature review on cancer patient decision aids to assess their effectiveness in supporting decisions related to fertility preservation. The results showed that decision aids enhanced awareness of fertility preservation, alleviated decisional conflict, and garnered high satisfaction ratings. As research continues to advance, an increasing number of relevant primary studies have emerged. However, in the routine assessment of such studies for clinical application, we have yet to observe systematic, comprehensive, and integrated research outcomes. The purpose of this study is to gain a deeper understanding of the specific impacts of decision-aid tools on reproductive outcomes and to comprehensively and systematically evaluate the actual effects of these tools in cancer patients. Additionally, we aim to identify potential new influencing factors and key determinants of reproductive decision-making that have not been previously mentioned in similar studies. Ultimately, we will utilize the concepts of acceptability, adoption, appropriateness, feasibility,fidelity, cost, penetration, and sustainability to conduct a comprehensive, multidimensional assessment of the application of decision aids, thereby providing a more comprehensive set of research results.

Materials and Methods

Data Sources and Study Selection

The systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines [38]. Inclusion Criteria: 1) fertility decision support tools as an intervention affecting reproductive outcomes in cancer patients; 2) patient involvement must be present in the development, assessment, implementation, and evaluation phases of fertility decision support tools; 3) in cases where multiple reports exist for the same study, the most recent research was included. If the same data was reported with different emphases, the study was still included; 4) forms of intervention included, but were not limited to, printed materials (such as pamphlets), online resources (such as websites), computer-based tools, or video-based resources; 5) both English and Chinese language literature were considered. Exclusion Criteria: 1) Literature reviews, books, unpublished articles, commentaries, protocols, conference abstracts, and research plans; 2) Literature meeting inclusion criteria but with data that could not be extracted.

Search Strategy

The literature search was conducted in August 2023, encompassing a total of 14 databases, including MEDLINE, CINAHL, PubMed, PsycINFO, Embase, Scopus, Web of Science, AMED, Cochrane, Google Scholar, CNKI, WanFang Data, VIP, and Sinomed. Duplicate articles were screened using EndnoteX 9.3.3. Two researchers conducted a joint review, browsing through the titles and abstracts of the literature before proceeding with full-text readings. In the event of any discrepancies, a third expert was consulted for adjudication.2.3 | Data extraction, quality assessment and synthesis

Data Extraction, Quality Assessment and Synthesis

Data extraction was carried out by two scholars. In the event of any discrepancies, a third party was consulted for resolution. The extracted information included general details and specific research outcomes. General details encompassed authorship, country of origin, study type, research phase, participant demographics, sample size source, research methodology, and data collection time points. Specific research outcomes included the type of decision aid tool, primary research objectives, measurement tools, and study results. Data related to implementation outcomes, as described by Proctor et al. (2011) [39], were extracted based on eight conceptually distinct implementation outcomes, which encompassed acceptability, adoption, appropriateness, feasibility, fidelity, implementation cost, penetration, and sustainability. It was deemed necessary to track and evaluate these cited references to ensure the report’s completeness. The included studies underwent quality and risk bias assessments using the Mixed Methods Appraisal Tool (MMAT). Each study was subjected to data synthesis based on two screening questions and five assessment criteria. In cases of score discrepancies, reviewers engaged in discussions until consensus was reached. This review strategy has been registered and is available on PROSPERO (ID: CRD42023452239).

Results

Study Selection

We employed a systematic literature search strategy, covering multiple databases and yielding a total of 2660 potentially relevant articles. These included MEDLINE (347 articles), CINAHL (172 articles), PubMed (422 articles), PsycINFO (23 articles), Embase (698 articles), Scopus (85 articles), Web of Science (618 articles), AMED (1 article), Cochrane (71 articles), Google Scholar (17 articles), CNKI (20 articles), WanFang Data (176 articles), VIP (2 articles), and Sinomed (8 articles). Subsequently, we utilized Endnote X9.3.3 software to screen and remove all duplicate records, resulting in the exclusion of repeated literature. Following this, a meticulous initial screening of titles and abstracts was conducted for 1619 articles. At this stage, we ultimately selected 123 articles for full-text reading. Two researchers independently reviewed the literature to ensure its content aligned with the research theme and type. During the process of full-text reading, a total of 112 articles were excluded. The reasons for exclusion included irrelevance to the research theme, unavailability of the full text, inconsistency in study type, and inclusion of research plans and conference abstracts, among others. During the process of including literature, any discrepancies were adjudicated by a third expert to ensure the rigor and accuracy of the research. Ultimately, we included 11 articles that met the objectives and requirements of our study. The specific search strategy can be found in the PRISMA flow diagram.

Study Quality

We conducted quality assessments for each included publication using the Mixed Methods Appraisal Tool (MMAT) standard. MMAT assesses the quality of qualitative or quantitative studies, with scores ranging from 25% (meeting one criterion) to 100% (meeting all criteria). In this study, the overall quality of the included research was relatively high. Specifically, seven studies achieved a quality score of 100%, while the remaining studies scored 80%. The lower scores were primarily attributed to poor reporting of methods in RCT studies, particularly in the aspects of randomization and allocation concealment.

Study Characteristics

Table 1 and Table 2 summarize the general characteristics and specific content of the included studies. The 11 selected articles span the years from 2012 to 2022 and were conducted in various countries or regions, including one from the United Kingdom [40], two from China [41,42], two from Australia [34,43], three from Switzerland [14,44,45], one from Germany [46], and two from the Netherlands [47,48]. These studies encompass a diverse range of types, consisting of five randomized controlled trials (RCTs) [14,42-44,47], three non-randomized controlled studies (N-RCTs) [45,46,48], two mixed-method studies [40,41], and one quantitative cross-sectional study [34]. The primary phases of the studies predominantly focus on the implementation of effects, with a total of 10 articles addressing this aspect [14,34,40-42,44-48], followed by tool development (2 articles) [41,45], feasibility (2 articles) [40,47], and acceptability (1 article) [43]. In total, 1300 subjects were involved in these studies, covering various types of cancer with a primary focus on breast cancer.

Table 1: General characteristics of 17 trials of patient decision-aids for cancer patient.

Table 2: Overview of Included Decision Aids, Treatment Coverage, Outcome Measures, and Key Findings.

Decision‐Aid Characteristics

Decision aid tools were incorporated in the studies in various formats: four studies utilized paper-based tools [34,40,43,46], three studies employed online-based tools [14,45,48], three studies were based on web platforms [41,44,47], and one study did not specify the type of decision aid tool used [42].

Effect of Decision‐Aids on Decisional Outcomes

Fertility-related Knowledge

Six studies investigated the impact of fertility decision support systems on patients’ fertility-related knowledge. This includes two randomized controlled trials (RCTs) [44,47], two non-randomized controlled trials [45,46], one cross-sectional study [34], and one quasi-experimental study [48]. These studies employed researcher-developed questionnaires for measurement. In these studies, Peate et al.’s research [34] found no significant difference in knowledge scores between the intervention and control groups at one month, but at 12 months, the DA group had lower knowledge scores compared to the routine care group. Ehrbar et al.’s study [45] indicated that after fertility preservation knowledge counseling (T1), there was no significant difference in knowledge between the two groups. However, in the aspect of “egg freezing,” the intervention group showed significantly higher knowledge and confidence. Conversely, a recent study [44] discovered no significant difference in patients’ knowledge about existing fertility preservation methods between the two groups. On the other hand, Borgmann-Staudt et al.’s study [46] demonstrated that in terms of impaired fertility and preservation knowledge, patients in the intervention group had higher average knowledge scores than the control group at both 3 months post-diagnosis (T0) and 6 months post-diagnosis (T1), but these differences were not significant at both time points. Garvelink et al.’s study [47] found significant differences in knowledge between baseline and 6 weeks post-baseline (T1), as well as between baseline and 6 months post-baseline (T2). However, there were no significant knowledge differences between the intervention group and the control group. Additionally, Garvelink et al.’s study [48] pointed out that different types of decision support tools did not significantly affect the time spent using the tool and the number of pages viewed. However, regardless of the type of tool used, they significantly elevated the level of knowledge, resulting in an 81% relative increase. Furthermore, there was a positive correlation between the time spent using the tool and the level of knowledge.

Decision Conflict

Among the 7 studies evaluating the impact of fertility decision support tools on decision conflict, the study designs included 3 randomized controlled trials (RCTs) [14,42,47], 1 non-randomized controlled trial [45], 1 mixed-methods study [40], 1 quasi-experimental study [48], and 1 cross-sectional study [34]. These studies employed the Decisional Conflict Scale for assessment. Jones et al.’s study [40] showed that that the level of decision conflict in the control group was generally below the average level. Huang et al. [42] assessed the impact of oncology fertility education for breast cancer nurses and patients on decision-conflict. The results indicated that, with similar scores on the Fertility Intention Scale (FIS) among patients, the experimental group had significantly lower decision conflict scores than the control group. Peate et al. [34] used the Decisional Conflict Scale for decision conflict measurement and found that participants receiving the DA experienced a significantly greater reduction in decision conflict over 12 months compared to participants receiving standard care. At 1 month, the average difference in DCS between the two groups was negligible, but at 12 months, the DA group had lower Decisional Conflict Scale scores than the routine care group. Additionally, Ehrbar et al.’s study in 2019 [14] found that participants who had already made a decision about fertility preservation after consultation (T1) had significantly lower decision conflict scores. The intervention group had significantly lower decision conflict scores compared to the control group. At 1 month after consultation (T2), the intervention group also had significantly lower decision conflict scores in total and on both sub-scales compared to the control group. However, 12 months after consultation (T3), the decision conflict difference between the two groups was no longer significant. Furthermore, Ehrbar et al.’s 2018 study [45] found that the intervention group had slightly higher overall decision conflict scores than the control group, but these differences were not significant. In another study, Garvelink et al.’s results [47] showed that women who received the booklet scored significantly lower on the “effective decision” sub-scale compared to women who received the decision aid (DA). Finally, Garvelink et al.’s study [48] found that women who used the values clarification exercise had a significantly different tool use time compared to those who did not use it, but there was no difference compared to those who were unable to use the exercise. Women who used the exercise performed better in decision conflict, value clarification, decision support, and informed decision.

Decision Regret

In the included literature, a total of four studies addressed decision regret, including three randomized controlled trials (RCTs) [14,44,47] and one cross-sectional study [34]. These studies all employed the Decisional Regret Scale (DRS) for measurement. The study by Peate et al. [34] observed that at one month, there were no significant differences in DRS scores regarding fertility-related decisions between groups. However, at twelve months, after adjusting for educational levels, participants who received Decision Aid (DA) exhibited significantly lower levels of decision regret. On the other hand, findings from the studies by Ehrbar et al. in 2019 and 2021 [14,44] indicated that patients in both intervention and control groups reported overall low levels of decision regret, with the intervention group consistently lower than the control group. However, these differences did not reach statistical significance. It is noteworthy that at one month post-consultation (T2), no significant correlation was found between decision conflict and decision regret. However, at twelve months post-consultation (T3), a strong correlation emerged. Contrastingly, the study by Garvelink et al. [47] found no statistically significant differences in anticipated regret between measurement time points or between groups. It is worth noting that both groups exhibited a slight trend of increased regret between baseline assessments after six weeks (T1) and six months (T2), although this increase was not significant.

Information Satisfaction

Incorporated into the research are three studies that delve into information satisfaction. These include one randomized controlled study [14], one non-randomized controlled study [45], and one cross-sectional study [34]. The assessment tools utilized in these studies were custom-designed questionnaires by the researchers. Peate et al.’s study [34] found that participants who underwent decision aid (DA) were more satisfied with information regarding the impact of breast cancer treatment on fertility and different fertility options. Ehrbar et al.’s 2018 research [45] demonstrated that decision support tools were considered helpful in the decision-making process, with the majority of participants expressing willingness to recommend them to other women. Their 2019 study likewise affirmed [14] that DA participants reported higher satisfaction levels and perceived the use of DAs as beneficial.

Fertility Intentions

In addressing the influence of decision support tools on fertility intentions, we included a total of three randomized controlled trials [14,42,44]. One study utilized the Fertility Intentions Scale (FIS) for measurement [42], while the remaining two employed patient-designed questionnaires. Huang et al.’s study assessed changes in patients’ fertility intentions using the FIS scale after employing decision support tools. The results revealed that, with similar scores on the Fertility Intentions Scale (FIS), the experimental group exhibited significantly lower decisional conflict scores compared to the control group. This indicates the effectiveness of decision-support tools in reducing decisional conflict. Ehrbar et al.’s study [14] found a notably higher positive attitude towards fertility preservation compared to a negative attitude, with no significant differences between the two groups. Additionally, attitudes and willingness to undergo fertility preservation remained stable over time, demonstrating consistency and stability in patients’ attitudes towards fertility preservation. Furthermore, Ehrbar et al.’s 2021 research [44] arrived at similar conclusions. They observed significantly higher positive attitudes in both groups compared to negative attitudes. The control and intervention groups showed comparable scores in positive attitudes, negative attitudes, and willingness to utilize fertility preservation methods. Participants’ attitudes and intentions towards fertility preservation remained stable from post-consultation (T1) to 12 months post-consultation (T3), indicating that the impact of decision support tools on fertility attitudes and intentions remains consistent over a period of time.

Characteristics of Decision Support Tools

In the evaluation of fertility decision support tools, we included a total of four studies, comprising two randomized controlled trials [43, 44] and two mixed-method studies [40,41]. Jones et al. [40] assessed the utility of the decision tool using the QQ-10 scale and ultimately concluded that the CFM tool is acceptable and highly beneficial for women making decisions regarding fertility preservation treatment. Additionally, Huang et al. [41] developed an electronic system for tumor fertility protection and examined its comprehensibility, feasibility, and usability. The study found high usability ratings from both patients and healthcare providers. Furthermore, the social support questionnaire assessment indicated effectiveness of the tool in providing information and practical support, particularly for breast cancer patients. Ussher et al. [43] evaluated the perceived acceptability and impact of the intervention. The results showed that the majority of participants gave positive feedback on the educational resources, considering them easy to understand, user-friendly, containing relevant information, and addressing fertility concerns more effectively than other sources of information. Moreover, Ehrbar et al.’s [44] study reached similar conclusions. They found significantly higher positive attitudes in both groups compared to negative attitudes. The control and intervention groups showed comparable scores in positive attitudes, negative attitudes, and willingness to use fertility preservation methods. Participants’ attitudes and intentions towards fertility preservation remained stable from post-consultation (T1) to 12 months post-consultation (T3), with no significant changes observed.

Others

Fertility decision support tools play a positive role in decision readiness [40,41], family involvement [34,46], informed consent [34,48], social support [41], and health literacy [43], providing robust support and guidance for patients facing decisions about fertility preservation treatment. However, we encountered different results in terms of quality of life. Within the context of fertility decision-making, we observed relatively limited coverage of various aspects under this theme. Nevertheless, despite the relatively small number of studies involved, we were able to identify some intriguing patterns and draw some conclusions based on existing data. Therefore, we conducted a comprehensive review based on logical grouping, highlighting the following key themes: decision readiness, family involvement, informed consent, social support, health literacy, and quality of life. First and foremost, decision readiness emerged as a crucial topic. Research indicates that decision support tools play a positive role in enhancing patients’ level of decision readiness. By employing these tools, patients gain a more comprehensive understanding of information related to fertility preservation treatment, providing a solid foundation for their decision-making process. Jones et al.’s study [40] found that fertility decision support tools were considered acceptable and highly beneficial for women preparing to make decisions about fertility preservation treatment. Additionally, Huang et al.’s 2022 study [41] emphasized the importance of providing ample knowledge about breast cancer and related treatments, addressing participants’ concerns about fertility and fertility preservation choices. Furthermore, family involvement and support also play an indispensable role in the decision-making process. Studies suggest that the active participation of partners or family members can alleviate patient anxiety and have a positive impact on decision outcomes. Obtaining support from family members during the decision-making process provides patients with additional confidence and peace of mind, enabling them to make decisions that align with their own wishes. Borgmann-Staudt et al.’s study also confirmed that specially designed educational materials about fertility preservation improved the knowledge and autonomy of both patients and parents [46]. However, Peate et al.’s study found no significant difference in partner involvement between the two groups [34]. Additionally, having a comprehensive understanding of relevant information is crucial for making informed decisions. By thoroughly comprehending various pieces of information during the decision-making process, patients can better grasp the implications and consequences of various choices, allowing them to make fertility preservation decisions that align with their individual circumstances. Garvelink et al.’s study also emphasized the importance of information, with women using value clarification exercises performing better in decision conflict, value clarification, decision support, and informed decision-making [48]. The effectiveness of social support networks also plays a crucial role in the decision-making process. When facing decisions about fertility preservation treatment, receiving assistance from social support networks helps patients better understand and address various issues, providing strong support for the decision-making process. Huang et al.’s study found that providing ample knowledge about breast cancer and related treatments was crucial for participants in making decisions about fertility and fertility protection [41]. Lastly, having good health literacy is an essential component of the decision-making process. It helps patients better understand and participate in the decision-making process, enhancing their capacity for making informed health decisions. The study found that after the intervention, patients’ health literacy significantly improved, including functional, interactive, and critical health literacy [43]. It’s worth noting that in the included studies, intervention had different expected outcomes on participants’ quality of life, with no change or varying degrees of decline observed. Jones et al. [40] assessed the quality of life of women facing decisions about preserving fertility after receiving a cancer diagnosis using the EQ-5D-3L scale. The baseline EQ-5D-3L average scores indicated lower levels of problems in five quality of life domains. Apart from daily activities (p = 0.018), there were no other significant differences in quality of life scores based on EQ-5D data before and after receiving CFM. Ussher et al.’s study noted that at the baseline stage, the Health Promotion (HP) group, through self-intervention with educational resources, had significantly higher quality of life scores than the Standard Health (SH) group, showing a statistical difference. However, after the intervention, both groups experienced a decline in quality of life, with the SH group’s average quality of life score significantly lower than that of the HP group.

Implementation Results

Among the studies included, at least seven provided data on implementation results (see Table 3 Additional file 6). A total of five studies discussed acceptability [14,34,40,43,45], three discussed adoption [14,41,45], one discussed appropriateness [43], and two discussed feasibility [41,47]. Other aspects were not addressed, including fidelity, cost, penetration, and sustainability. The measurement method primarily involved surveying patients. In terms of acceptability, our main focus was focused on the perspectives of patients, healthcare providers, or other stakeholders to determine whether there was widespread acceptance and satisfaction. In the five included studies, researchers assessed participants’ satisfaction with fertility decision support tools through self-made questionnaires [14,34,40,43,45]. In terms of adoption, the attention was on the extent of implementation strategy dissemination across different organizations or regions. In the three studies included, one study measured this through the System Usability Scale (SUS) Scores questionnaire [41], and all three results indicated willingness to propagate and use this tool [14,41,45]. Appropriateness considered contextual factors, such as patient characteristics and healthcare environments, to assess the suitability of the strategy. Only one study measured results in this aspect, showing that clinical healthcare providers had confidence in recommending the tool’s use to patients [43]. Feasibility focused on resource feasibility and implementation feasibility assessments, including potential obstacles and challenges. Two studies addressed this theme, and the research results both showed that the tool is feasible and effective, with potential for further validation through large-scale studies in the future [41,47].

Discussion

In this study, we conducted a systematic review of the impact of fertility decision support on fertility outcomes in cancer patients. The outcome indicators primarily covered fertility knowledge, decisional conflict, decision regret, information satisfaction, fertility intentions, and tool characteristics. Additionally, we discovered a range of new research findings, including the effects on patient decision-making preparedness, family involvement, patient informedness, social support, patient health literacy, and quality of life. Upon comprehensively analyzing the application of decision support tools in clinical practice, we observed that the majority of studies primarily focused on assessing the acceptability, adoption, appropriateness, and feasibility of the tools. The fertility decision support system has shown a certain impact on patients’ knowledge related to fertility preservation. However, this impact is influenced by multiple factors and requires continuous optimization and improvement in practice. Additionally, specific support for fertility preservation and its long-term effects need further research and attention. From the research results, there is considerable heterogeneity, and the impact on fertility knowledge is time-dependent, yielding different results at different times. Peate et al.’s study [34] found that the fertility decision support system did not have a significant impact on knowledge scores in the short term, but in the long term, the DA group’s knowledge scores were significantly lower than than those of the standard care group. Future research should pay more attention to and optimize the long-term effects of fertility decision support systems. Furthermore, Garvelink et al.’s study [48] indicates that different types of decision-support tools do not significantly affect the time spent using the tool or the number of pages viewed. However, regardless of the type of tool used, they significantly increase knowledge levels, with a relative increase of 81%. This underscores that the design of decision support tools may be more important than specific types, as their primary function is to enhance patients’ knowledge levels.

Decision conflict is an issue that cancer patients need to pay attention to when facing the decision of fertility preservation. Decision support tools can reduce the level of decision conflict in patients to some extent. However, there are certain differences in results under different research conditions, so the application of decision support tools needs to be considered comprehensively according to specific situations in practice. At the same time, long-term tracking and evaluation are also necessary to understand the persistence and stability of the decision. Huang et al.’s study shows that after receiving cancer fertility education, the decision conflict scores of the experimental group were significantly lower than those of the control group, indicating that an improved education level can make patients more clear about their choices when making decisions [42]. The results of Peate et al.’s study present an interesting trend. In the short term, the difference in decision conflict between the two groups is not significant [34]. However, with long-term observation, patients receiving decision support were significantly lower than those receiving routine care, indicating that fertility decision support tools play a positive role in the long-term decision-making process. On the other hand, Ehrbar et al.’s study also found that after consultation, participants who had already made the decision to preserve fertility had significantly lower decision conflict scores, and the decision conflict scores of the intervention group were also significantly lower than those of the control group. However, after long-term follow-up, the difference in decision conflict between the two groups was no longer significant, which may be because the stability of the decision gradually tended to be consistent over time. The analysis of multiple studies shows that the overall level of decision conflict is relatively low, indicating that fertility decision support tools can provide effective support, reducing the contradictions and confusion in the decision-making process. Decision regret is a complex and multidimensional psychological state in the process of fertility preservation treatment decision-making. Different research results may be influenced by various factors, including individual characteristics, education level, and the timing of using decision support tools. In future research, it may be considered to further explore these influencing factors in order to provide more targeted decision support and intervention measures to alleviate the potential decision-regret emotions that patients may face. Decision support tools have achieved significant effectiveness in providing fertility-related information, enabling patients to have a clearer understanding of reproductive knowledge. The discussion of information satisfaction in the study focuses on evaluating the effectiveness of decision support tools in helping patients obtain fertility-related information and the satisfaction of patients with this information. At the same time, patients’ satisfaction with the use of decision support tools is also high, and they are willing to recommend them to other women. This provides strong support for the further promotion and application of decision support tools. Peate et al.’s research results show that participants who received decision support were more satisfied with information regarding the impact of breast cancer treatment on fertility and different reproductive choices [34]. This indicates that decision support tools play a positive role in providing information, enabling patients to have a more comprehensive understanding of reproductive knowledge. The multiple studies by Ehrbar et al. [14,45] also indicate that patients participating in decision support are satisfied with the use of the tool and believe that it has a positive impact on their decision-making process. However, it is worth noting that there are certain differences in results under different research conditions, so the application of decision support tools needs to be comprehensively considered according to specific situations in practice to ensure that patients can obtain the maximum level of information satisfaction. The decision support tool has achieved positive results in influencing the willingness for fertility preservation, reducing the patients’ decision conflict, and maintaining a positive attitude towards fertility preservation. This provides strong support for the application of decision support tools in clinical practice. It also reminds us that in the design and implementation of decision support tools, it is important to provide patients with comprehensive and clear information about fertility preservation to better assist them in making decisions that align with their own intentions. The results of Huang et al.’s study [42] indicate that the experimental group had significantly lower decision conflict scores compared to the control group. This suggests that the decision support tool has achieved significant effectiveness in reducing patients’ decision conflict. It is evident that the decision support tool provides patients with more comprehensive and clear information about fertility preservation, enabling them to have a clearer understanding of their choices. Additionally, the studies by Ehrbar et al. in 2019 and 2021 [14,44] show that participants’ attitudes towards fertility preservation were significantly more positive than negative, and this attitude remained stable over time. This indicates that patients’ attitudes towards fertility preservation are relatively stable and consistent. The decision support tool did not change the patients’ attitudes but rather provided additional information based on their existing attitudes.

The decision support tool has demonstrated significant effectiveness in providing fertility preservation information and support, offering strong assistance for patients to make decisions in line with their own preferences. This underscores the importance of considering patients’ needs and providing easily understandable, user-friendly, and comprehensive information when designing and implementing decision support tools, in order to better assist patients in their decision-making process. The study by Jones et al. [40], which utilized the QQ-10 to assess the usability of the CFM tool, yielded results indicating that the tool is acceptable and highly useful for women preparing to make decisions about fertility preservation treatment. This indicates the tool’s effectiveness in providing information and support. Additionally, the electronic system for tumor fertility protection developed by Huang et al. [41] received positive evaluations in terms of comprehensibility, feasibility, and usability. Both patients and healthcare providers considered it highly usable. Furthermore, the tool demonstrated effectiveness in providing information and practical support, particularly for breast cancer patients. In the research on fertility preservation decision support tools, we have made intriguing new findings that play a positive role in decision preparedness, family involvement, informed consent, social support, health literacy, and quality of life. Firstly, decision preparedness has been confirmed as a crucial issue. Decision support tools actively contribute to enhancing patients’ level of decision preparedness. By utilizing these tools, patients can gain a more comprehensive understanding of information related to fertility preservation treatment, providing a solid foundation for decision-making. Particularly, in the study by Jones et al. [40], fertility preservation decision support tools were deemed acceptable and highly useful for women preparing to make decisions about fertility preservation treatment. Secondly, family involvement and support play an indispensable role in the decision-making process. The active participation of partners or family members can alleviate patient anxiety, positively influence decision outcomes, and garnering support from family members can provide patients with added confidence and reassurance, enabling them to make decisions that align with their preferences more resolutely. Furthermore, having a thorough understanding of relevant information is crucial for making informed decisions. By comprehensively understanding various pieces of information during the decision-making process, patients can better grasp the impacts and consequences of various choices, thereby making fertility preservation selections that align with their individual circumstances. The effectiveness of a social support network also plays a vital role in the decision-making process. Receiving assistance from a social support network can help patients better comprehend and address various issues, providing robust support for decision-making. Finally, having good health literacy is an essential component of the decision-making process. It aids patients in better understanding and participating in the decision-making process, elevating their capacity for making health-related decisions. The research found that after intervention, patients’ health literacy significantly improved, including functional, interactive, and critical health literacy [43]. Regarding quality of life, the reasons behind changes in quality of life after fertility preservation decision support will also need to be further explored in the future. In summary, though research on these aspects is relatively limited, we have uncovered numerous intriguing patterns and conclusions from existing data. Decision preparedness, family involvement, informed consent, social support, health literacy, and quality of life are all crucial topics worthy of attention in the fertility preservation treatment decision-making process. The positive impacts of these aspects provide robust support and guidance for patients when facing decisions about fertility preservation treatment, further promoting the rationality and personalization of medical decisions. These new findings offer valuable references for future research and clinical practice.

Clinical Limitations

While we have made comprehensive efforts to discuss the application of fertility preservation decision support tools in clinical settings in this study, it is important to acknowledge that there are still some limitations in certain aspects. Firstly, in terms of factors such as credibility, cost, penetration, and sustainability, there may be insufficient data or the ability to provide a comprehensive summary in the current research. However, we can propose some potential improvement suggestions from the perspective of future research and practice. It is recommended to consider tool reliability as a crucial assessment criterion in future studies and explore how to ensure the stability and credibility of the tool in practice. Additionally, from the standpoint of technological progress and development trends, discussing how to reduce the cost of the tool to promote its widespread clinical application is worthwhile. Furthermore, strengthening the promotion and training of this tool is also an important initiative to increase its prevalence in clinical practice. It is essential to think about how to ensure the tool remains effective in long-term use, such as through regular updates and enhancements. For other aspects of the discussion, it should be noted that not all possible scenarios have been covered in the current research. In future studies, further exploration of these aspects will be necessary to gain a comprehensive understanding of the effectiveness of fertility preservation decision-support tools in clinical practice. Despite our best efforts to address these limitations in this study, it is crucial to exercise caution when generalizing these results to other contexts.

The limitations of this study include the potential for significant bias and contradictory results due to inconsistent assessment criteria in the measurement methods employed. This limitation could impact the accurate understanding and assessment of the psychological state in the decision-making process regarding fertility preservation treatments. Furthermore, factors such as sample selection and study design may introduce selection bias and extrapolation constraints, thereby restricting the generalizability and applicability of the study’s findings to a certain extent. Therefore, the inconsistency in measurement methods within the study may lead to contradictions among research outcomes. This underscores the need for future research to carefully and meticulously select appropriate measurement tools while taking into full consideration various potential influencing factors in order to enhance the reliability and robustness of research results. This study, based on existing data and our inclusion methodology, has made every effort to ensure comprehensiveness. However, given the breadth of the research field and the nature of database searches, we acknowledge the possibility that some studies, especially those conducted under specific conditions, may not have been included. Nevertheless, we believe that this does not diminish the uniqueness and importance of our study. Given the current limitations of this research, we encourage future researchers to continue exploring this field. We believe that such efforts will contribute to enriching and refining the knowledge base in this area, providing more comprehensive and effective support for future clinical practices.

Clinical Implications

Firstly, through a comprehensive analysis of the latest research findings, we can provide clinical practitioners with an up-to-date and authoritative body of scientific evidence to support the development and application of fertility decision-making tools. Secondly, it can facilitate patient involvement in decision-making. Fertility decisions are highly personalized and sensitive topics, making patient involvement crucial. By furnishing patients with scientific foundations, we empower them with more agency and confidence, enabling active participation in the decision-making process. This not only ensures that patients feel heard but also enhances their trust in treatment options, thereby improving the overall efficacy of the treatment process. Additionally, we can assist patients in better comprehending the various influencing factors of fertility decisions through information and education, enabling them to make more informed choices. Lastly, our research provides practical guidance and decision support. Clinical healthcare providers can tailor the most appropriate fertility decision plans for each patient based on this scientific evidence, thus maximizing patients’ fertility aspirations. Simultaneously, patients can, with this evidence, participate more confidently in the treatment process, thereby collectively achieving the most desirable treatment objectives.

Conclusion

The primary objective of this study is to explore the tangible impact of fertility preservation decision aid tools (PtDAs) among cancer patients. Through a comprehensive assessment encompassing various aspects such as fertility-related knowledge, decision conflicts, post-decision regret, information satisfaction, fertility intentions, and tool characteristics, this research furnishes robust evidence for a deeper understanding of the practical implications of PtDAs within the cancer patient population. It offers valuable insights for clinical nursing practices, potentially serving as a valuable complement to current fertility care practices. Beyond clinical counseling, this research aims to ensure the fulfillment of the demand for high-quality information and support.

Declarations

Ethical Approval and Consent to Participate

Not applicable

Funding

No funding

Availability of Data and Materials

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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Effect of Tonisity Px™ Administration on Pre-weaning Mortality Under Field Conditions: A Meta-Analysis

DOI: 10.31038/IJVB.2024822

Abstract

Modern sows are characterized by a high prolificacy as indicated by the increased number of total born piglets, which results in a higher pre-weaning mortality. Tonisity Px (TPx) is an isotonic protein drink administered to piglets from d2 to d8 of life during the suckling period to support intestinal health and development. The aim of the present study was to analyze the effects of TPx administration on the pre-weaning mortality under field conditions in 10 sow farms in Belgium and the Netherlands. Therefore, 10 sow farms with a pre-weaning mortality between 3.3 and 13.8% were enrolled in the study. Supplementation of Tonisity Px was compared with standard Control treatment in the same batch. Number of piglets on d2 and the day before weaning was counted and pre-weaning mortality was calculated. Subsequently, reduction in pre-weaning mortality between Control and Tonisity Px group was calculated at farm level. Based on these results, a scatterplot was designed and a trendline formula for the effect of Tonisity Px was calculated. Applying the trendline formula, an economic calculation was run to find the weaned piglets and end-nursery piglet market price for a positive return-on-investment (ROI = or > 1). Supplementation of Tonisity Px resulted in a significant reduction (P = 0.003) of pre-weaning mortality from 7.38 to 5.41%, which is a 23.40% reduction in pre-weaning mortality. Economic analysis revealed that Tonisity Px supplementation has a positive economic return-on-investment from 6.0% pre-weaning mortality onwards under the current end-nursery 25 kg piglet market prices. In conclusion, supplementation of Tonisity Px from d2-8 in the suckling period results in a 23.4% reduction in pre-weaning mortality with a positive return-on-investment from 6.0% pre-weaning mortality onwards.

Keywords

Tonisity Px, Pre-weaning mortality, Field results, Meta-analysis

Introduction

Modern sows are characterized by a high prolificacy as indicated by the increased number of total born piglets (TBP). Under Danish conditions, the number of TBP has increased from 12.9 in 2000 to 19.6 piglets per litter in 2020 [1-4]. Modern sows may commonly wean 33-35 piglets per sow per year, but herds with the highest productivity now wean more than 40 piglets per sow per year. The increased litter size is, however, accompanied by a clear decrease in the average piglet birth weight [5-9]. Moreover, due to the limited amount of available colostrum, a decrease in colostrum volume consumed per piglets could be observed [5,12]. This may increase the vulnerability of piglets born from modern high prolific sows [8], which in turn decreases livability from farrowing to weaning. In addition, the small intestine of newborn piglets undergoes major developmental changes during the first 10 days of life. Therefore, this critical period has been identified as a ‘window of opportunity’ for potential nutritional interventions to support the development of intestinal structure, including digestion, absorption and growth, and the maturation of the immune system resulting in potential lifelong effects [3,6,10,11]. These factors create an opportunity to provide supplemental nutrition in the first days of the piglets’ lives to increase livability. Tonisity Px™ (TPx) is a highly palatable isotonic protein solution that provides microenteral nutrition to the intestinal cells. Tonisity Px™ is administered as a 3% solution to neonatal piglets for a 7-day period from day 2 after birth (d2) until day 8 after birth (d8). Tonisity Px™ has been demonstrated to improve intestinal morphology with taller villi (+ 8.3%) and a thicker mucosal layer (+ 9.0%) by d9 in suckling piglets [7]. Furthermore, administration of TPx increased the abundance of beneficial bacterial populations, such as Lactobacillus and Bacteriodes species, and reduced potentially pathogenic bacterial populations, such as Escherichia coli and Prevotellaceae, in the pre-weaning period [1,2]. The aim of the present study was to analyze the effects of TPx administration during the suckling period from d2 to d8 on the pre-weaning mortality under field conditions in 10 sow farms in Belgium and the Netherlands.

Materials and Methods

Test Ingredient

The test ingredient consisted of an isotonic protein solution (Tonisity Px™; Tonisity Ltd, Dublin, Ireland), which provides easily-absorbable nutrients (glucose, amino acids, and peptides) and electrolytes that can be used directly by the enterocytes.

Study Population

Ten farrow-to-wean sow farms in Belgium and the Netherlands with an average number of 733 ± 182 productive sows (min. 200, max. 2000) were enrolled in the field study (Table 1).

The sow herds were run according to different batch-management systems (BMS), such as 1-week BMS (n = 2), 3-week BMS (n = 1), 4-week BMS (n = 6), and 5-week BMS (n = 1). The piglets were weaned at an average age of 23 ± 0.82 days of age (min. 21, max. 26). The average pre-weaning mortality was 7.4 ± 1.1% (min. 3.3, max. 13.8). All sow herds were high prolific with 15.5 live born piglets (LBP) and 32.1 piglets weaned per sow per year.

Table 1: Description of the relevant farm characteristics (obtained prior to the study enrollment) of all 10 sow farms included in the trial comparing standard piglet treatment to supplementation of Tonisity Px (Tonisity Ltd, Dublin, Ireland).

Farm ID

# Sows Breed BMS1 Weaning age % PWM2 LBP3 PSY4

Standard program

A

800

DanBred

4

21

7.4

15.67

32.60

Electrolyte solution

B

250

Topigs-Norsvin

1

26 3.9 14.83

31.23

No supplementation

C

400

Topigs-Norsvin

4

21 10.0 14.53

29.22

No supplementation

D

200

DanBred

4

21 4.9 16.41

35.17

No supplementation

E

1,150

DanBred

1

26 13.8 16.00

30.38

Water

F

2,000

Topigs-Norsvin

4

21 3.3 15.52

33.72

No supplementation

G

1,000

DanBred

4

21 5.3 16.61

35.47

No supplementation

H

1,000

DanBred

4

21 5.3 14.82

33.17

No supplementation

I

280

Hypor

3

26 8.6 15.01

29.45

No supplementation

J

250

Topigs-Norsvin

5

28 11.3 15.45

30.12

No supplementation

1BMS: Batch Management System
2PWM: Pre-Weaning Mortality
3LBP: Live Born Piglets
4PSY: Piglets Weaned per Sow per Year

Experimental Design

Litters within the same farrowing batch were allocated to one of 2 groups, Control or supplementation with TPx. The allocation was balanced according to sow parity (gilts vs. older sows) and number of LBP. In 8 out of 10 sow herds, the piglets in the Control group did not receive any supplementation. However, in farm A, the Control group received a supplementation with a standard electrolyte solution, and in farm E, the Control group was supplemented with water during the study period from d2 to d8. Litters in the TPx group were given 250 mL of 3% TPx solution on d2 of age, and from d3-8 of age TPx litters received 500-600 mL of 3% TPx once daily in a clean waterbowl.

Measurements

The number of piglets per litter was counted at d2, the start of TPx administration, and at the day prior to weaning. Pre-weaning mortality was calculated per litter and per batch as the number of dead pigs pre-weaning divided by the number of piglets at d2.

Meta-Analysis

The PWM results obtained in the Control and TPx group were plotted and a trendline was calculated for both the Control and TPx group. Based on the trendline formula of the TPx group, a simulation was performed on potential PWM reduction within the range of 4 to 15% PWM under field conditions. These data were subsequently applied to run an economic calculation for return-on-investment (ROI) of the test product.

Economic Calculations

Return-on-investment calculations were performed based on the number of extra piglets per 1000 piglets enrolled by TPx administration. The cut-off value of weaned and end-nursery piglet market price was calculated for a ROI value of 1.

Therefore, the following formula was used based on the cost of treatment for 1000 piglets enrolled: y = 390 / x, with x = number of extra piglets per 1000 piglets enrolled and y = cut-off value of weaned piglet market price. The cut-off value of end-nursery piglet market price was calculated by adding € 25.00 to the cut-off value of weaned piglet market price.

Statistical Analysis

Data were analyzed using JMP 17.0 and results were significant at P < 0.05.

Results

Pre-weaning Mortality

The results on pre-weaning mortality in both Control and TPx groups, including the overall percentage of reduction in pre-weaning mortality in the 10 farms enrolled in the study are given in Table 2.

Supplementation of TPx resulted in a significant (P = 0.003) reduction in PWM as compared to the Control group. In the Control group, PWM was between 3.3 and 13.8%, whereas in the TPx group PWM was between 2.7 and 8.6%. The overall percentage of reduction varied between 5.1% at minimum and 37.7% at maximum.

Table 2: Pre-weaning mortality and overall reduction in pre-weaning mortality in the farms enrolled in the study evaluating Tonisity Px supplementation from day 2 to 8 versus a standard on-farm program for the neonatal piglets.

Farm ID

PWM control (%) PWM Tonisity Px (%)

% PWM reduction

A

7.4 5.7 23.0
B 3.9 3.7

5.1

C

10.0 5.6 44.5
D 4.9 3.3

32.7

E

13.8 8.6 37.7
F 3.3 2.7

17.2

G

5.3 4.7 10.8
H 5.3 4.0

23,8

I

8.6 8.6 10.9
J 11.3 8.1

28.3

Pre-weaning Mortality According to Breed, Weaning Age and Number of Live Born Piglets

Further detailed analysis of PWM according to breed, weaning age and number of live born piglets in both Control and TPx group are given in Table 3.

For sow breeds, DanBred sows in the Control group had an average PWM of 7.99% in contrast to other breeds (Topigs-Norsvin, Hypor) had a PWM of 6.47%. In the TPx group, both sow breeds had a lower PWM of 5.73% and 4.92% for DanBred and other breeds, respectively.

For weaning age, litters weaned at 21 days of age had a lower PWM (6.03%) as compared to litters weaned at a later age of 26-28 days (9.41%) in the Control group. In the TPx group, PWN decreased to 4.33% and 7.02% for litters weaned at 21 and 26-28 days of age, respectively.

For number of live born piglets, litters with an LBP < 16 piglets had a lower PWM (6.92%) as compared to litters with an LBP ≥ 16 (7.84%) in the Control group. In the TPx group, PWM decreased to 5.00% and 5.82% for litters with an LBP < 16 and an LBP ≥ 16, respectively.

Table 3: Detailed analysis of overall percentage of PWM in control and Tonisity Px supplemented group, considering sow breed (DanBred vs. other breeds), weaning age (early 21 d vs. late 26-28 d), and number of live born piglets (low LBP < 15.5 vs. high LBP ≥ 15.5). Significant differences at P < 0.05 are indicated with a different letter in supercript.

Parameter

PWM control (%) PWM Tonisity Px (%)

% PWM reduction

All farms

7.38 ± 1.11

5.41 ± 0.67

23.40 ± 4.01

Sow breed      
DanBred

7.99 ± 1.52

5.73 ± 0.89

26.04 ± 3.79

Other breeds

6.47 ± 1.71

4.92 ± 1.10

19.44 ± 8.71

Weaning age      
21 d

6.03 ± 1.98

4.33 ± 0.50a

25.33 ± 4.85

26-28 d

9.41 ± 2.12

7.02 ± 1.12b

20.51 ± 7.55

Live born piglets
LBP < 16

6.92 ± 1.84

5.00 ± 1.04

24.27 ± 4.91

LBP ≥ 16

7.84 ± 1.41

5.82 ± 0.91

22.52 ± 6.92

Meta-analysis of Pre-weaning Mortality Data

The scatterplot of percentage PWM in Control and TPx group of the 10 farms enrolled in the study demonstrates the reduction in PWM percentage following supplementation of TPx from d2 to d8 (blue trendline) as compared to the PWM in the Control group (orange line) (Figure 1). The trendline formula obtained based on the results was: y = 0.5581 x + 0.0129 with an R² of 0.8561. This trendline formula will be used in the simulations for the economic calculation of ROI following supplementation of TPx in different scenarios of PWM percentages.

Figure 1: Scatterplot of percentage PWM in Control and Tonisity group of the10 farms enrolled in the study. Orange squares, datapoints of the Control group; blue squares, datapoints of the Tonisity Px supplemented group in relation to their initial percentage of PWM. Trendline shows the correlation between initial percentage of PWM (Control) and the percentage of PWM obtained following supplementation with Tonisity Px.

Economic Calculations

The simulation of PWM reduction following supplementation of TPx based on the trendline formula obtained in relation to the initial on-farm PWM with calculation of the number of extra pigs per litter and per 1000 born piglets based on the PWM reduction is given in Table 4. Simulation with the obtained trendline formula using an initial PWM ranging from 4.0% to 15% resulted in calculated PWM with TPx application from 3.52% to 9.66%, which was equal to a PWM reduction percentage of 11.9 to 35.6%. Based on these numbers, the number of extra piglets per litter and per 1000 piglets born were calculated. At 4.0% initial PWM, a reduction of 11.9% resulted in 0.08 extra piglets per litter and 5 extra piglets per 1000 piglets born.

Applying the formula y = 390/x, we obtained a weaned piglet price at ROI = 1 breakpoint of € 81.66 and of € 106.66 for end-nursery piglet price. Based on current market prices for weaned piglets and end-nursery piglets (20 September 2024; Flemish piglet price), TPx supplementation has an ROI of 1 or more starting from a PWM percentage of at least 6.0% (indicated by the dotted red line on the figure) (Figure 2).

Table 4: Simulation of PWM reduction following supplementation of Tonisity Px based on the trendline in relation to the initial on-farm PWM with calculation of the number of extra pigs per litter and per 1000 born piglets based on the PWM reduction. Calculation of weaned piglet price and piglet price end-nursery (25 kg) in relation to the return-on-investment breakpoint (ROI = 1.0) based on the average cost of Tonisity Px for 1000 supplemented piglets.

Initial PWM

PWM Tonisity Px Simulated PWM reduction Extra piglets/litter Extra piglets per 1000 piglets born Weaned piglet price at ROI = 1 breakpoint (€)

Piglet price end-nursery at ROI = 1 breakpoint (€)

4.0%

3.52% -11.9% 0.08 5  € 81.66  € 106.66
5.0% 4.08% -18.4% 0.15 9  € 42.41

 € 67.41

6.0%

4.64% -22.7% 0.22 14  € 28.65  € 53.65
7.0% 5.20% -25.8% 0.29 18  € 21.63

 € 46.63

8.0%

5.75% -28.1% 0.36 22  € 17.37  € 42.37
9.0% 6.31% -29.9% 0.43 27  € 14.51

 € 39.51

10.0%

6.87% -31.3% 0.50 31  € 12.46  € 37.46
11.0% 7.43% -32.5% 0.57 36  € 10.92

 € 35.92

12.0%

7.99% -33.4% 0.64 40  € 9.72  € 34.72
13.0% 8.55% -34.3% 0.71 45  € 8.75

 € 33.75

14.0%

9.10% -35.0% 0.78 49  € 7.96  € 32.96
15.0% 9.66% -35.6% 0.85 53  € 7.31

 € 32.31

fig 2

Figure 2: Analysis of return-on-investment breakpoint (ROI = 1) related to market price of weaned piglets (6 kg; orange bars) and piglets at end of nursery (25 kg; green bars). The dashed red line is set at the piglet price (25 kg, end of nursery) of € 56.50 which is the current market price for end-nursery 25 kg piglets (20.09.2024; Flemish piglet price).

Discussion

Supplementation of Tonisity Px from d2 to d8 of life resulted in a significant (P = 0.003) reduction of PWM as compared to a simultaneous Control group in 10 farms with difference in management approach under field conditions. This observation is in line with previous studies on the effect of TPx (Carlson et al., 2019). In 8 out of 10 farms, PWM reduction due to TPx was compared to a non-supplemented Control group, whereas in 2 farms a standard supplementation of plain water or electrolyte solution was applied in the Control group. Moreover, the effect of TPx supplementation was evaluated in different sow breeds, such as DanBred (n = 5), Topigs-Norsvin (n =4) and Hypor (n = 1). These breeds are known to be highly prolific which can be confirmed by the high number of LBP (15.01 to 16.41 LBP per litter) and the number of piglets weaned per sow per year (29.22 to 35.47 PSY). As expected, farms with an already low PWM could only observe a mild to moderate further reduction in PWM (5-10%), whereas farms with a rather high PWM had a major reduction in PWM (37-44%).

Detailed analysis on TPx effect related to sow breed, weaning age and number of LBP revealed that in all scenarios, TPx supplementation resulted in a decrease of PWM percentage as compared to the Control. As observed in practice, DanBred sows have a higher PWM as compared to other breeds such as Topigs-Norsvin and Hypor. As expected, TPx supplementation resulted in a higher PWM reduction (26.04%) in DanBred sows as compared to other sow breeds (19.44%). Litters weaned at 26/28 days of age had a more than 50% higher PWM both in the Control and TPx group as compared to litters already weaned at 21 days of age. There is no clear explanation for this observation. Since most of the PWM occurs in the first 3-5 days of life, length of the lactation period should not further impact PWM. The difference in PWM for litters with more or less than 16 LBP was very limited, as was the reduction in PWM following TPx supplementation. Indeed, all 10 selected farms were highly prolific and therefore the range of LBP was quite limited (15.01 to 16.41 LBP per litter).

Analysis of the scatterplot of PWM percentage in the Control and TPx group resulted in a trendline formule of y = 0.5581 x + 0.0129 with 85.61% of the changes in y (PWM supplementing TPx) that could be explained by changes in x (PWM under standard control situation). Application of this trendline formula in a simulation with control PWM ranging from 4.0 to 15.0% resulted in a presumed PWM supplementing TPx ranging from 3.52 to 9.66%. It could be observed that a gradual increase in PWM reduction was present with higher initial PWM. Based on these data both the number of extra piglets per litter and per 1000 piglets born could be calculated (Table 4). These data were used to calculate the minimal piglet market value for a ROI of 1, both in weaned piglets, which are not regularly sold onto the market under our local Belgian and Dutch conditions, and end-nursery piglets sold at 25 kg standard weight. Further comparison of these end-nursery piglet prices to the current piglet market prices (Flemish pig price, 20.09.2024) demonstrated that TPx supplementation can result in a positive ROI (ROI equal to or higher than 1) from 6.0% PWM onwards.

Conclusions

The administration of TPx from d2 to d8 during lactation resulted in a significant reduction of PWM in 10 farms under field conditions in Belgium and the Netherlands. Supplementation of TPx resulted in a positive ROI (= or > 1) when PWM at farm level was equal to or higher than 6.0% under current end-nursery piglet market prices.

Abbreviations

PWM: Pre-Weaning Mortality; TPx: Tonisity Px™; d2: Day 2 After Birth; d8: Day 8 After Birth; TBP: Total Born Piglets; LBP: Live Born Piglets; ROI: Return-On-Investment

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A Modified Palatoplasty for Palate Cleft: A Case Report and Literature Review

DOI: 10.31038/JDMR.2024722

Abstract

Introduction: Cleft palate is a common congenital defect with several described surgical repairs. It is generally an isolated congenital abnormality but can be associated with multiple syndromes. Although there are a multitude of surgical options, many are variations of a previously described repair, and the most successful treatment modality remains a controversy.

Case Summary: The patient, a man, age 25 years old, had a Class III cleft lip and palate Veau classification, underwent a modified palatoplasty and acquired a favourable palatopharyngeal closure function, decreased hemorrhage and swelling.

Conclusion: In this study, we provide a modified palatoplasty for all palate cleft variations, it may benefit for uvula intact, reduce bleeding and swelling.

Keywords

Congenital cleft palate, Modified palatoplasty, Cleft palate repair

Introduction

Cleft of the palate, CP, is one of the most prevalent orofacial birth defects around the world occurring in about 0.33 in every 1000 live births regardless of race, and there was no significant difference between men and women [1,2]. The cleft palate is generally an isolated congenital abnormality but can be associated with other anomalies or multiple syndromes, with or without the presence of lip or alveolar clefting [3]. According to the Veau classification, the cleft palate is divided into four groups depending on the extent of involvement: Group I is limited to the soft palate only; Group II involves the soft and hard palates; Group III includes the soft and hard palate as well as the lip; and Group IV is bilateral complete clefts Figure 1 [4].

fig 1

Figure 1: Veau classification. A class I. defects of the soft palate only; B class II. Defects involving the hard palate and soft palate; C class III. Defects involving the soft palate to the alveolus, usually involving the lip; D class IV. Complete bilateral clefts.

Congenital palate defect is caused by disturbed embryonic development when the palatal shelves fail to fuse during the 6th~12th week of pregnancy [5]. It is multifactorial, influenced by genetic factors recessive or incompletely dominant polygenic inheritance and exogenous factors drugs, folic acid deficiency, viral infections, etc [6]. It has been difficult to point to a single etiologic mechanism responsible for this complex trait, resulting in severe speech, nutrition, and mental and social developmental disorders that significantly reduce patients’ quality of life [7].The diagnosis of cleft palate is not difficult because of its obvious features. Treatment of cleft palate ordinarily requires multiple interventions spanning time from birth to adulthood [8]. However, current treatment for this disease generally demands early surgery and face reconstruction procedures that may be revised during childhood and infancy, causing a great number of patient complaints and economic burdens on health systems that need to be minimized [9]. In this study, we report a modified operation of palatoplasty that provides a choice for these patients to shorten operation time, and reduce intraoperative bleeding, trauma, and postoperative swelling.

Case Report

A 25-year-old Chinese man came with a congenital cleft of lip and palate, he received lip repair in the local hospital when he was 4 years old. However, palatal repair was suspended because of a lack of money. Nowadays, the patient was referred to our hospital for palatal cleft repair which significantly affects pronunciation. The patient denied other abnormal parts of the body and his parents are both normal. After comprehensive examination and imaging evaluation by a professional maxillofacial surgeon, he was diagnosed with CP group III, Class III skeletal pattern malocclusion, microdontia, defect of dentition, and dental cavity Figure 2. At this time, the patient only wanted to receive palatal cleft repair.

fig 2

Figure 2: Clinical information of the patient. A-C the profile photo of the patient; D-F the itro-oral film of the patient; G the computerized tomography imaging of the patient.

A cleft of the soft and hard palate with cleft lip postoperative was seen in our patient. Our modified palatoplasty involves: 1. relaxing incisions along the lateral edge of the hard palate, starting anteriorly near the palatomaxillary suture line, going posteriorly just medial to the alveolar ridge, and ending lateral to the hamulus, approximately to the tuberosity of the alveoli. 2. The incision posterior to the maxillary tuberosities was widened by blunt dissection, the hamulus was identified and the hamulus pterygoideus was broken. 3. The mucosa along the edges of the cleft starting at the palatal alveolar to anteriorly 5 mm of uvula was also incised Figure 3A and 3B. 4. The entire mucoperiosteum was then raised from the oral surface of the hard palate; care was taken to preserve the two neurovascular pedicles, the greater palatine pedicle posteriorly and the incisive pedicle anteriorly. Thus, bi-pedicled mucoperiosteal flaps were created on both sides of the cleft Figure 3C. 5. Three layers, including an oral mucosal layer, muscle layer, and nasal layer were dissected which tends to relieve tension on the repair and reduce the postoperative fistula rate. 6. Firstly, the nasal side of the cleft was closed, using redundant mucoperiosteum from the incision along the cleft edge Figure 3D. 7. Secondly, residual mucosa along the edges of the cleft uvula fissa was incised, and seamed the nasal layer. 8. Next, the muscle layer was closed approximately using an intravelar veloplasty. 9. Lastly, the bi-pedicled oral mucosal flaps were approximated to cover the oral surface of the cleft Figure 3E. A month later, the patient returned to our clinic, the palatine mucosa was integrity and the uvula recovered Figure 3F. The speech quality of this man was also improved and had a good velopharyngeal function (Figure 4).

fig 3

Figure 3: Surgical procedures of the patient and postoperative manifestation. A-E the operative procedues of the patient; F one month postoperative follow-up of the patient.

fig 4

Figure 4: Traditional surgery and modified operation. (A) a-c the traditional surgery of the palatoplasty; (B) d-g the modified surgery of the palatoplasty.

Discussion

The goals of palatoplasty are to acquire complete and intact closure of the palate and restoration of the velopharyngeal sphincter. Besides, reducing hemorrhage, avoiding palatal fistula, and decreasing postoperative swelling also should include care. After decades, there are many techniques for cleft palate repair and each has its advantages. To repair the soft palate, Intravelar Veloplasty, and Furlow Double-Opposing Z-Plasty are widely applied [10,11]. To repair the hard palate, the Von Langenbeck Palate palatoplasty, Veau-Wardill-Kilner palatoplasty, Two-Flap palatoplasty, and Vomer Flap techniques are employed around the world [11-14]. Nonetheless, the most successful treatment modality remains controversial. According to Veau classifications, surgeons are recommended to choose appropriate surgical techniques for the patients after evaluating the results as they see fit to provide the best functional outcomes for their patients [15]. However, all the techniques above mentioned may cause uvula injury due to incision without suture immediately and improve the occurrence of velopharyngeal incompetence. The rate of oronasal fistula following primary cleft palate surgery was about 3.8~6.1% [16]. In this study, we raise a modified palatoplasty: delayed incision of the uvula and earlier suture of the nasal layer. It is beneficial for uvula integrity, reducing uvula tears, and decreasing hemorrhage and swelling.

Fusion of particular orofacial structures during early gestation is required for proper development of the upper lip and jaw. Failure of this process leads to an orofacial cleft, which manifests as a gap in the tissue of the upper lip, the palate, or both [17]. Treatment of cleft lip and palate ordinarily requires multiple interventions spanning the time of birth to adulthood [18]. This process includes a multidisciplinary evaluation, involving pediatric dentists, oral and maxillofacial surgeons, orthodontists, prosthodontists, speech therapists, and psychological consultation teachers. In this study, our patient only underwent the necessary surgery because of financial difficulty, we sincerely advise he achieve serial therapy shortly.

Conclusion

We preferred the modified palatoplasty for all cleft variations. The use of modified palatoplasty in the cleft palate seems to contribute to a reduction of hemorrhage, uvula varies, and postoperative swelling.

Acknowledgement

Cailing Jiang contributed to the conception, design, analysis and interpretation of data, and drafting of this article. Chong Jiang, Zijun Guo and Haiyou Wang contributed to data collection and analysis. Sui Jiang contributed to the conception and design, critical review of the article, and final approval.

Declaration

The authors declare no conflict of interest.

Funding

The preparation of this manuscript was not supported by any funding or grants.

Ethics Approval

Ethics approval was received from the ethics committee of Guangdong Provincial People’s Hospital (KY2023-827-03).

References

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  15. Liu H, et al. (2021) A new congenital cleft palate New Zealand rabbit model for surgical research. Sci Rep 11: 3865.
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Prognostic Modeling of Gynecological Complications in Tamoxifen Therapy

DOI: 10.31038/CST.2024934

Abstract

The risk of endometrial hyperplasia (EH) increases during adjuvant therapy of breast cancer (BC) with tamoxifen. Currently, the problem of endometrial hyperplasia and endometrial cancer due to long-term use of tamoxifen is relevant, since the incidence of endometrial pathology has a direct correlation with the duration of use of tamoxifen. In order to improve early detection of endometrial cancer and avoid unnecessary invasive procedures, surveillance by a gynecologist should be tailored to the risk of endometrial cancer in women who have had breast cancer.

We developed a prognostic model to determine the likelihood of developing a composite endpoint (polyp, endometrial hyperplasia, abnormal uterine bleeding) depending on anamnestic and genetic risk factors. A comprehensive association analysis using mathematical modeling allowed us to build a predictive model of the risk of developing such adverse events as endometrial hyperplasia, endometrial polyp and abnormal uterine bleeding. This prognostic model has demonstrated high diagnostic efficiency, which allows its implementation in the clinical practice of gynecologists.

Keywords

Tamoxifen, Endometrial hyperplasia, Endometrial polyp, Abnormal uterine bleeding, Predictive modeling

Introduction

Breast cancer (breast cancer) is hormone-dependent in 60-70% of cases. Due to the fact that estrogens enhance cell proliferation of hormone-dependent breast tumors, endocrine therapy with tamoxifen (TAM) or aromatase inhibitors (IA) is an important stage in the treatment of such patients [1,2]. According to the literature, taking tamoxifen for 5 years reduces the risk of breast cancer recurrence by 39% [3]. The use of tamoxifen may be limited due to the adverse drug reactions (ADR). It is known that the adjuvant breast cancer therapy with tamoxifen increases the risk of endometrial hyperplasia (EH) because tamoxifen acts as an antagonist of estrogen receptors on breast tissue and as an agonist on the endometrium [4]. According to Neven P. and Vernaeve H. 50% of women who received long-term TAM treatment experienced any adverse effects on the endometrium [5]. Currently, the problem of hyperplastic processes and endometrial cancer is especially relevant during long-term tamoxifen administration, since the frequency of endometrial pathology has a direct correlation with the duration of TAM administration [6]. The supervision of a gynecologist should be adapted to the risk of endometrial cancer in women who have undergone breast cancer in order to improve the early detection of endometrial cancer and avoid unnecessary invasive procedures.

The Purpose of the Study

To determine the prognosis of tamoxifen ADR including endometrial hyperplastic processes, endometrial polyps and abnormal uterine bleeding, based on mathematical modeling in conjunction with the carrier of polymorphic variants of genes of cytochrome P450 enzyme and drug transporter proteins.

Hypothesis

Women with breast cancer taking endocrinotherapy have predictors of the development of local gynecological symptoms that require additional attention from an obstetrician-gynecologist. These predictors are not only clinical factors, but also genetic determinants responsible for the metabolism and transport of tamoxifen.

Materials and Methods

A prospective clinical and epidemiological and simultaneous pharmacogenetic study involved 120 patients with luminal breast cancer of stage I-III who were on adjuvant TAM therapy. Anamnestic, clinical, laboratory and instrumental data obtained from a survey of patients and extracts from medical records (results of the last hospitalization) were analyzed. The collection of biological material for genetic research (double buccal scraping) was carried out simultaneously in the Clinic named after Professor Y.N. Kasatkin in 2018-2019 years in Moscow. Informed voluntary consent was signed by all participants of the study before taking the genetic material. Polymorphic variants of the CYP2D6, CYP2C, and CYP3A genes were studied: CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, as well as the polymorphic marker of the ABCB1 gene (C3435T) encoding the P-glycoprotein. Polymorphic gene variants were determined by the polymerase chain reaction method in real time at the Russian Medical Academy of Continuing Professional Education (RMACPE) of the Ministry of Health of the Russian Federation. The study was approved by the Ethics Committee of the RMACPE of the Ministry of Health of the Russian Federation (Protocol No. 1 dated 17.01.2017) and was conducted in accordance with the legislation of the Russian Federation and international regulatory documents. The program SPSS Statistics 26.0 (USA) was used for statistical processing of the results. The normality of the distribution was checked by the Kolmogorov–Smirnov method with the Lilliefors correction. The intergroup differences were assessed using the Student’s t-test and the Mann-Whitney U–test. Comparative analysis was used using either Pearson’s χ2 or Fisher’s exact test. To form mathematical predictive models, the method of constructing a logistic function using binary logistic regression with step-by-step selection of factors and, if necessary, additional construction of ROC curves followed by ROC analysis was used.

Results and Discussion

Tamoxifen’s ADR structure contains both systemic and local ADR, and systemic ones dominate over local ones with the highest representation of tides as vasa-active symptoms from the autonomic nervous system (67.3%). Local gynecological symptoms are represented by endometrial hyperplasia (GE), abnormal uterine bleeding (AMC) and endometrial polyp (PE) are much less common (20.2%; 12.5% and 12.5%, respectively), but in total they amount to 45.2%, which, taking into account a low subjective assessment (frequent asymptomatic course, absence of complaints), requires close attention from obstetricians and gynecologists. The high percentage of local gynecological symptoms we obtained turned out to be close to the data of Neven P and Vernaeve H., indicating 50% of any adverse effects on the endometrium in women taking TAM [5]. Taking into account the high total frequency of occurrence of local gynecological symptoms (%EH+%AUB+%PE=45.2%) and the presence of reliable associative links between local and systemic ADR, as well as genetic and non-genetic parameters obtained earlier [7-9], we developed a prognostic model to determine the development of a combined endpoint (polyp, endometrial hyperplasia, abnormal uterine bleeding). The resulting model included 9 predictors, taking into account the determination coefficient of the Neidlekerk, included 40% of the factors determining the development of the combined endpoint, and was reliable (p<0.001). The observed dependence is described by the equation:

for

where p is the probability of developing a combined endpoint (polyp, endometrial hyperplasia, AUB) (in fractions of one); XWeight loss – Weight loss during TAM therapy, kg; XMenopause – menopause (0 – no, 1 – yes) ; XAge– age, years ; XAsthenia – asthenia (0 – no, 1- yes); Xnumber of births – number of births; Xnumber of pregnancies – number of pregnancies; XABCB1 3435_TT – TT genotype of polymorphic variant ABCB1 3435 (0 – no, 1 – yes); XCYP2D6_4_GG– GG genotype of polymorphic variant CYP2D6*4 (0 – no, 1 – yes); XCYP3A5_GG– GG genotype of polymorphic variant CYP3A5 (0 – no, 1 – yes).

Based on the values of the regression coefficients, factors such as weight loss, the presence of asthenia, an increase in the number of births, the presence of the TT genotype of the polymorphic variant ABCB1 3435, the presence of the genotype GG of the polymorphic variant CYP2D6*4, GG of the polymorphic variant CYP3A5 have a direct relationship with the probability of developing a combined endpoint. While the presence of menopause, an increase in the number of pregnancies in the anamnesis and an increase in age reduce the likelihood of developing a combined endpoint. Table 1 shows the parameters of the relationship of each of the predictors of the model, including both clinical and anamnestic data and genetic factors responsible for metabolism and transport of TAM, with the chances of developing a combined endpoint of local gynecological symptoms.

Table 1: Evaluation of the relationship between the predictors of the model and the chances of developing a combined endpoint of local gynecological symptoms.

Predictor

COR (95% Cl) p AOR (95% Cl)

p

Weight loss

2.4 (0.93-6.13)

0.07 2.94 (0.98-8.8)

0.054

Menopause

0.55 (0.23-1.3)

0.160 0.5 (0.14-1.8)

0.302

Age

0.96 (0.9-1.01)

0.113 0.97 (0.89-1.05)

0.393

Asthenia

3.2 (1.3-7.3)

0.009* 3.78 (1.3-11)

0.014*

Number of births

1.8 (1.02-3.1)

0.041* 2.94 (1.13-7.66)

0.027*

Number of pregnancies

0.97 (0.76-1.2)

0.804 0.689 (0.42-1.12)

0.132

ТТ ABCB1 3435

2.77 (1.16-6.6)

0.021* 1.85 (0.64-5.3)

0.255

GG CYP2D6*4

2.6 (1.07-6.4)

0.035* 5 (1.6-15.6)

0.006*

GG CYP3A5

1.15 (0.49-2.7)

0.746 1.9 (0.66-5.59)

0.227

*The association with the predictor is statistically significant.

To confirm the results obtained, the most optimal value of the predictive function P was additionally determined using ROC analysis and a ROC curve was constructed (Figure 1).

Figure 1 is a ROC curve characterizing the dependence of the forecast of the combined endpoint on the value of the logistic function P. The area under the ROC curve was 0.827±0.043 (95% CI: 0.743-0.911). The value of the logistic function P at the cut-off point was 0.273. Patients with P values equal to 0.273 or higher were predicted to have a high risk of developing EH, endometrial polyp and AUB, and with P <0.273, a low risk. The sensitivity of the model at the selected cut-off point value was 82.4% (28 correct predictions out of 34 cases of combined endpoint), specificity was 72.9% (51 correct predictions out of 70 cases of absence of combined endpoint development). The overall diagnostic efficiency is 76%. According to the results, independent predictors of the development of the combined endpoint are the presence of asthenia, the number of births, the presence of the genotype GG polymorphic variant CYP2D6*4, the genotype TT polymorphic variant ABCB1 3435 and GG polymorphic variant CYP3A5.

fig 1

Figure 1: A ROC curve characterizing the dependence of the forecast of the combined endpoint on the value of the logistic function P.

Conclusion

The conducted complex associative analysis allowed us, using mathematical modeling, to construct a prognostic model of the risk of developing combined local gynecological symptoms, such as endometrial hyperplasia, endometrial polyp and AUB. These local gynecological symptoms are a natural manifestation of the pharmacodynamic effects of tamoxifen, as an agonist of estrogen receptors on the endometrium in women with breast cancer. The result obtained determines the need for increased alertness of obstetricians and gynecologists regarding endometrial hyperplastic processes in women with breast cancer undergoing tamoxifen endocrinotherapy and, accordingly, the development of measures for their prevention. In addition, this predictive model has demonstrated high diagnostic effectiveness, which allows it to be implemented in the clinical practice of an obstetrician-gynecologist, including through medical decision support programs.

References

  1. Huang B, Warner M, Gustafsson JA (2015) Estrogen receptors in breast carcinogenesis and endocrine therapy. Mol Cell Endocrinol. [crossref]
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Endotoxin Challenge: Optimizing Experimental Models for Antipyretic Drug Development

DOI: 10.31038/IDT.2024521

Abstract

The endotoxin challenge serves as a valuable experimental model for antipyretic drug development, providing insights into systemic inflammatory responses and the efficacy of novel treatments. By inducing predictable physiological reactions, it mirrors the inflammatory profile of sepsis, allowing for investigations into the pathophysiology of fever and inflammation, as well as the evaluation of antipyretic therapies. This review examines the varied applications of endotoxin administration, particularly intravenous bolus dosing, and highlights the potential of combined bolus-infusion paradigms to sustain systemic responses and better align with therapeutic pharmacokinetics and pharmacodynamics. Furthermore, mathematical modeling and simulation techniques offer innovative approaches to optimizing experimental designs and data analysis. Despite its broad application, there remains a need for models that elicit a safe, sustained, and measurable systemic response, allowing for the thorough evaluation of antipyretics. Developing such models is crucial to enhancing the efficiency of drug development and improving clinical management of pyrexia across various settings.

Keywords

Endotoxin challenge, Antipyretic drug development, Systemic inflammation, Experimental medicine models, Pharmacokinetic – pharmacodynamic optimization

Introduction

The endotoxin challenge is an experimental medicine tool that has been used for over a century across a number of investigational efforts and in some settings even as a therapeutic. Kamisoglu et al. have shown that the plasma metabolomic profile following an endotoxin challenge is concordant with that from sepsis survivors, affirming the validity of the endotoxin challenge as a viable model to recapitulate homeostatic responses to inflammatory and pyrogenic challenges [1]. Uses of the endotoxin challenge in clinical investigation include attempts to characterize pathophysiology of pyrexia and inflammatory and anti-inflammatory pathways, describe time-course of clinical and molecular events as well as assessment of the degree of benefit of novel anti-pyretic and anti-inflammatory therapies. The doses and routes of endotoxin administration vary depending on the scientific question at hand. In turn, there are some challenges to design of an endotoxin challenge tailored to address specific questions, particularly in the context of definition of quantitative estimates of therapeutic benefit.

The innate risk of administering endotoxin especially to healthy volunteers is partly balanced by the somewhat predictable nature and time-course of the systemic response it elicits [2]. To further deliver on the twin need to ensure safe use of endotoxin for investigational purposes as well as to guide drug development, the NIH and FDA jointly oversaw an effort to develop a “national biological reference standard to be made available to pharmaceutical manufacturers and qualified biomedical investigators as an aid to standardization of bioassays and research with endotoxin”. This standard developed using endotoxin from Escherichia coli O: 113: H10: K negative has also been adopted by the WHO as its reference for endotoxin assays [2].

Pyrexia or fever is defined as a state in which the central thermoregulatory set point is increased, primarily via disinhibition of thermogenesis, and pyrogens are agents that induce pyrexia [3,4]. In general, exogenous pyrogens such as bacterial and viral antigens or exotoxins activate the Toll-like receptor (TLR) pathway, that triggers a signal transduction cascade leading to increased generation of endogenous pyrogens such as prostaglandins, culminating in the pathophysiologic events that constitute the pyrexia response [3,5]. The purported teleologic role of pyrexia in the setting of disease, particularly infectious disease, is an adaptive response to inhibit microorganism proliferation and amplify endogenous immunological response [6]. However, this is accompanied by increases in metabolic demand as well as undue stress on the cardiovascular, respiratory and other systems that are less than welcome [6]. Timely and prudent use of antipyretics tailored to rein in the unwarranted systemic effects of pyrexia without impacting its benefits as an adaptive response relies heavily on clinical judgment [6]. However, there is limited standardization to guide the use of antipyretics, particularly so from a contextual perspective [6]. It is also important to note that antipyretics themselves may carry side-effects and there is a paucity of data and limited interest in developing newer antipyretics [6]. Given that fever is one of the commonest clinical symptoms and signs, there is an urgent need to develop newer antipyretics with optimized time-action and benefit-risk profiles to enable fit-for-purpose use based on the setting in which fever occurs.

The sterile inflammatory state induced by an endotoxin challenge makes it especially valuable to characterize pyrexia and evaluate antipyretics. Although endotoxin may be administered by various routes, in the context of pyrexia, given the need to elicit a measurable systemic response, intravenous (IV) administration remains the preferred route. Systemic responses have been reported in settings of high and low dose administration. Following an IV endotoxin (E. coli O: 113) bolus in the range of 2 to 4 ng/kg body weight in healthy volunteers, Suffredini et al. and others reported a monophasic febrile response with onset 1 to 2 hours after administration, peaking at 3 to 4 hours to reach a maximal rise in body temperature over baseline with spontaneous resolution of the febrile response between 8 and 12 hours after the bolus administration [2,7]. In a placebo-controlled study, Pernerstorfer et al. were able to successfully demonstrate superiority of the antipyretic effects of acetaminophen over aspirin using a 4ng/ kg IV endotoxin bolus challenge [8]. Dose-limiting toxicities at doses greater than 4ng/kg have generally precluded their routine use. The brisk and robust febrile response following IV endotoxin at the 2-4ng/ kg dose is preceded by flu-like symptoms (chills, rigors, malaise, nausea and headache) starting one hour after administration and resolving spontaneously within 3 to 5 hours [2]. Other systemic changes accompanying the febrile response include a drop in blood pressure and increases in heart and respiratory rates with alterations in various blood- based measures including leukocytosis, cytokines and hormones [7]. It is important to note that while the rapid-onset responses are a direct effect of endotoxin, some of the other observed responses are a result of triggering of the inflammatory and cytokine cascade rather than a direct effect of the endotoxin itself, whose half-life when administered as an IV bolus is short lived. The IV bolus endotoxin challenge therefore allows for insights into the inflammatory event cascade and its mediators and at the same time also sheds light on whether a novel therapeutic has antipyretic or anti-inflammatory benefits. However, its ability to inform on the magnitude and duration of such benefit is particularly dependent on the synchrony between the temporal profile of action of the investigational agent and that of the responses to the endotoxin challenge. This is especially true for a novel antipyretic.

An alternate option would be administration of endotoxin as a continuous IV infusion to attempt to synchronize temporal profiles across the endotoxin challenge and investigational agent. However, the pharmacokinetics of a continuous infusion may limit the ability to achieve a peak challenge that is sufficiently robust to trigger a measurable systemic response. And indeed, Andreason et al. [9] have reported that lower doses of endotoxin in the range of 0.06-0.08 ng/kg, achieved via IV bolus or continuous IV infusion elicit what appears to be a submaximal inflammatory response with no detectable changes in vital signs including body temperature.

There is a need for development of a reliable yet feasible endotoxin challenge model that enables elicitation of a peak systemic response that is sustained over several hours, while not exceeding the total amount of endotoxin that can be safely administered and in a paradigm that is flexible enough to investigate a range of PK-PD profiles across agents and escalating doses. This need is particularly urgent in the context of novel antipyretics where onset and offset of effects and synchrony with the febrile response are critical parameters of success. One potential option would be a combined bolus-infusion approach, where a bolus administration of endotoxin is followed by a continuous infusion such that the total dose of endotoxin does not lead to dose-limiting toxicities. Van Lier et al. have proposed that a continuous infusion of endotoxin may better reflect the prolonged systemic responses including fever observed in the setting of infection and inflammation in man [10]. In a model of endotoxin challenge with a bolus dose of 1mg/kg followed by an infusion at 0.5ng/kg/hour for 3 hours, Jansen et al. were able to successfully demonstrate the beneficial anti-inflammatory effects of Cytosorb hemoperfusion in a group of healthy volunteers [11]. In a study with endotoxin challenges on two separate occasions, using a paradigm that combined a bolus administration of endotoxin at 1ng/kg followed by an infusion at 1ng/ kg/hour for 3 hours in a group of healthy volunteers, Leijte et al. were able to show endotoxin tolerance and reversal, confirming that the total dose administered in such a paradigm is safe and that the model is able to successfully detect treatment differences [12]. In a head-to- head comparison of a bolus only paradigm (2ng/kg) versus a combined bolus-infusion paradigm (1ng/kg bolus followed by a 3-hour infusion at 1ng/kg/hr) in the context of experimental endotoxemia, Kiers et al. found that subjects attained comparable peak levels and exhibited more prolonged and sustained duration of symptoms including fever during the endotoxin challenge model of a bolus followed by a continuous infusion vs bolus only method [13]. Kiers et al. also found that subjects attained higher peak cytokine levels that were sustained for longer durations following the combined bolus-infusion paradigm vs the bolus only paradigm [13]. Hence it is possible that a carefully developed combined bolus-infusion paradigm may permit administration of higher total amounts of endotoxin that could lead to a temperature response with slower onset but more sustained duration. Yet another novel approach would be to use modeling and simulation tools either as standalone approaches or in combination with in vivo efforts to optimize experimental paradigms and data analyses strategies. Using mathematical modeling of data collated across multiple endotoxin challenge experiments and investigator groups, Windoloski et al. showed that a continuous infusion elicits a stronger response that lasts longer than a bolus only paradigm, while potentially allowing for delivery of maximal total doses of endotoxin that can be safely administered [14]. Liu et al. have used mathematical modeling to describe and predict the dynamics of responses to endotoxin challenges with intent to inform on novel clinical trial design, particularly in the context of drug development [15].

Taken together, a combined bolus-infusion paradigm coupled with a mathematical modeling and simulation strategy may be the optimal solution to provide an experimental model of endotoxin challenge that is safe but provides a measurable response while allowing for synchronization with the PK-PD properties of a novel therapeutic. Although there is evidence that speaks to each component of the above approach, data to confirm validity of the approach and develop an integrated strategy are currently lacking. Therefore, there is an urgent need for targeted experimentation to address the above gaps and provide a consolidated strategy that integrates human in vivo experimentation and modeling and simulation tools that delivers on a fit-fit-for-purpose endotoxin challenge design.

References

  1. Kamisoglu K, Haimovich B, Calvano SE, Coyle SM, Corbett SA, et (2015) Human metabolic response to systemic inflammation: Assessment of the concordance between experimental endotoxemia and clinical cases of sepsis/SIRS. Critical Care 19. [crossref]
  2. Suffredini AF, Noveck RJ (2014) Human endotoxin administration as an experimental model in drug Clinical Pharmacology & Therapeutics 96: 418-422. [crossref]
  3. Bartfai T, Conti B (2010) The Scientific World JOURNAL 10: 490-503.
  4. Ogoina D (2011) Fever, fever patterns and diseases called ‘fever’ – A Journal of Infection and Public Health 4: 108-124. [crossref]
  5. Blatteis CM, Sehic E, Li S (2000) Pyrogen sensing and signaling: Old Views and new Clinical Infectious Diseases 31. [crossref]
  6. Mehmood KT, Al-Baldawi S, Zúñiga Salazar G, Zúñiga D, Balasubramanian S (2024) Antipyretic use in noncritically ill patients with fever: A Cureus.
  7. Godin PJ, Fleisher LA, Eidsath A, Vandivier RW, Preas HL, et (1996) Experimental human endotoxemia increases cardiac regularity. Critical Care Medicine 24: 1117- 1124. [crossref]
  8. Pernerstorfer T, Schmid R, Bieglmayer C, Eichler H, Kapiotis S, et al. (1999) Acetaminophen has greater antipyretic efficacy than aspirin in endotoxemia: A randomized, double-blind, placebo-controlled trial. Clinical Pharmacology & Therapeutics 66: 51-57. [crossref]
  9. Andreasen A, Krabbe K, Krogh-Madsen R, Taudorf S, Pedersen B, et al. (2008) Human Endotoxemia as a model of systemic inflammation. Current Medicinal Chemistry 15: 1697-1705. [crossref]
  10. van Lier D, Geven C, Leijte GP, Pickkers P (2019) Experimental human Endotoxemia as a model of systemic inflammation. Biochimie 159: 99-106. [crossref]
  11. Jansen A, Waalders NJ, van Lier DP, Kox M, Pickkers P (2023) CytoSorb hemoperfusion markedly attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo. Critical Care 27.
  12. Leijte GP, Kiers D, van der Heijden W, Jansen A, Gerretsen J, et (2019) Treatment with acetylsalicylic acid reverses endotoxin tolerance in humans in vivo: A randomized placebo-controlled study. Crit Care Med 47: 508-516. [crossref]
  13. Kiers D, Leijte GP, Gerretsen J, Zwaag J, Kox M, et (2019) Comparison of different lots of endotoxin and evaluation of in vivo potency over time in the experimental human ENDOTOXEMIA model. Innate Immunity 25: 34-45. [crossref]
  14. Windoloski KA, Janum S, Berg RM, Olufsen MS (2024) Characterization of differences in immune responses during bolus and continuous infusion endotoxin challenges using mathematical modelling. Experimental Physiology 109: 689-710. [crossref]
  15. Liu F, Aulin LB, Guo T, Krekels EH, Moerland M, et al. (2022) Modelling inflammatory biomarker dynamics in a human lipopolysaccharide (LPS) challenge study using delay differential equations. British Journal of Clinical Pharmacology 88: 5420-5427. [crossref]

Growth Rates, Feed Efficiency, and Condition Indices of Clarias gariepinus in Biofloc System Using Treated and Untreated Rice Bran as Carbon Sources

DOI: 10.31038/AFS.2024612

Abstract

The biofloc system uses the presence of microorganisms in the culture system to generate flocs from nitrogen waste, thus permitting continued water use. Factors like carbon source, carbon-to-nitrogen ratio, and stocking density affect the quality and density of microorganisms and the productivity of the system. This study aims to determine the growth, feed conversion ratio (FCR), and condition indices of catfish reared in a biofloc system using rice bran (RBB), fermented rice bran (FRB), and hydrolyzed fermented rice bran (HFRB) as carbon sources. Fingerling catfish with an initial mean weight of 11.15 ± 1.60 g were stocked in outdoor 200-liter plastic tanks in a randomized design with the three treatments in two replications. A biomass (g) to volume (l) ratio of 1:2 was maintained throughout the experiment. The carbon-nitrogen content was adjusted to 5:1 C-N in the system. The results showed that the water quality parameters of all the treatments were within the range recommended for aquaculture. The HFRB treatment showed significantly higher floc (P<0.05) compared with RBB and FRB. The weight of the catfish at the end of the 8-week rearing trials showed the catfish culture using RBB (80.26 ± 3.20 g), FRB (81.70 ± 2.5 g), and HFRB (85.50 ± 2.55 g) were significantly different (P<0.05). A similar trend was observed in the feed conversion ratio. The condition indices of catfish were also higher in FRB treatment. The FCR value and protein efficiency ratio were not significantly different (P>0.05) between RBB and HFRB treatments. However, the percentage survival was significantly lower in the HFRB treatment (P < 0.05) compared with the FRB and RBB treatments. While fermentation of rice bran has gained much consideration, this study demonstrated that acid-hydrolyzed fermentation of rice bran could boost its performance as a biofloc carbon source.

Keywords

Fermented rice bran, Acid-hydrolyzed rice bran, Biofloc, Carbon sources

Introduction

The African catfish, Clarias gariepinus, is valued as the most economically important fish cultured in Africa. This species is reputed for its desired aquaculture traits, including high fecundity, fast growth, hardiness, and market attractiveness. It is one of the most researched culturable fish in Nigeria. Modern culture techniques such as aquaponics and biofloc systems have also adopted catfish as one of the experimental species for the viability of the systems. Biofloc aquculture systems transform fish waste into microorganism biomass through the addition of carbon sources. The type of carbon source significantly influenced the water quality of the system. The floc serves as additional food for the fish, leading to faster growth and higher production of fish compared to traditional methods. Microorganism- enriched floc confers immunological enhancement to fish, thereby improving fish health. Many ingredients, such as grains, sucrose, sugarcane byproducts, tapioca, rice, wheat bran, etc., have been used as carbon supplements in biofloc systems. Ligno-cellulose materials like bran showed limited success in biofloc systems due to the to the slow release of carbon, but tends to have higher microbial diversity and immune-boosting potential for cultured organisms. Researcher efforts to improve carbon release and utilization of lignified and cellulose materials in biofloc systems remain pertinent. This work compared the growth performance and condition indices of catfish in biofloc systems where untreated, fermented, and hydrolyzed fermented rice bran were used as carbon sources. In ethanol production, acid hydrolysis of rice bran resulted in the conversion of its starch and cellulose component into reducing sugar, and fermentation has been used to increase the nutrient value of rice bran. While fermented rice bran has been well experimented with in biofloc, we hypothesize that acid hydrolyzed once could also serve in the system [1-12].

Materials and Methods

Experimental Setup

The experiment was conducted at the biological garden, Umaru Musa Yar’adua University. Fingerlings of African catfish, Clarias gariepinus, of 11.15 ± 1.50 g initial weight were obtained from hatchery-reared stock and kept in a 200-liter plastic tank for a 7-day acclimation period. The fish were fed a diet containing 40% crude protein at 5% body weight during 8:00–18.00 hours daily. Experimental tanks were seeded with 1 liter of water from a pre-fertilized earthen fish pond containing abundant phytoplankton. The fish were randomly distributed to the three experimental treatments of untreated, fermented, and hydrolyzed fermented rice bran biofloc in a triplicate of 20 fish per tank at a 2:1 biomass (g) to volume (l) ratio. Each experimental setup was seeded with 2 liters of water from a pre-fertilized earthen fish pond containing abundant phytoplankton.

Fermentation and Acid Hydrolysis of Rice Bran

Milled rice bran was sieved through a 0.50 mm sieve and sterilized in an autoclave. The solid-phase fermentation procedure described by [13] was followed with slight modifications. 50 g of rice bran was added to 45 ml of distilled water, while 5 g of baker’s yeast dissolved in 5 ml of water was added to make up a 1:1 weight-to-volume ratio of rice bran to water. The mixture was incubated in a beaker at a temperature of 27°C for 24 hours. Acid hydrolysis of rice bran was carried out using 50 ml of 2% sulfuric acid mixed with 50 g of rice bran, and the mixture was incubated at 90°C for 3.5 h. This was modified from. The hydrolyzed product was subjected to fermentation as described before. The fermented and hydrolyzed fermented products were oven dried at 45°C for 6 h, powdered, and sieved through 100 µm mesh. The fermented rice bran (FRB) and hydrolyzed fermented rice bran (HFRB) were used as carbon sources in biofloc production catfish [11].

Water Quality and Floc Monitoring

Water parameters were measured every two weeks. The temperature (°C) was determined using a mercury in glass thermometer, while the pH was measured using a Metrohm Herisau E520 pH meter. Dissolved oxygen concentration was determined through the Winkler-Azide method [14]. Chemical oxygen demand (COD) was determined titrimetrically, while biological oxygen demand (BOD) was determined using the incubation method at 20°C for five days [15]. The total ammonia nitrogen concentration was determined using the phenate method [16], while nitrate was determined using spectrophotometry [14]. By assuming 16% of protein is nitrogen and 46% carbon in rice bran, the amount of carbon to be added was calculated following. The total feed consumed per day was estimated, and the C:N was adjusted daily to 15:1 by adding treatments C of untreated, fermented, or hydrolyzed rice bran. The treatment carbon was mixed with 1 liter of water from the treatment before being added to the experimental setup. Biofloc volume (ml/L) was measured every 14 days for each experimental treatment using an Imhoff cone. The floc solution was allowed to settle down for one hour before the reading was taken [17-19].

Data Collection

The total length (TL) of fish in centimeters from each replicate was measured from the tip of the snout to the end of the caudal fin using a meter rule. Body weight was measured using an electronic digital balance. At the end of the experiment, all fish in the tank were counted, and the survival rate was determined. Growth performance in each treatment was estimated by weighing 10 randomly selected fish from each treatment and replicates on a biweekly basis, and the following growth and condition indices parameters were estimated:

Absolute growth (ΔG, g) = (W2 – W1), g.

Absolute growth rate (AGR, g/day)= (W2−W1)/t Relative growth (RG %) = (W2 – W1/ W1) × 100

Specific growth rate weight (%∕day) = (ln mean final weight − ln mean initial weight)/ no. of culture days ×100,

Where W1 is the initial mean weight (g), W2 is the final mean weight ( g), and t is the experimental duration.

Survival (%) = (Number of harvested fish/ number of stocked fish) × 100,

FCR = Total Feed fed (g)/Total wet weight gain (g).

Protein efficiency ratio PER = (Body weight gain g)/protein intake g)

Condition factor (CF) = [Body weight, g)/ Body length, cm3)] ×100 [20]

Hepatosomatic index (HIS) = (Liver weight, g)/(Whole body weight, g) ×100

Viscerosomatic index (VSI) = (Viscera weight, g)/ (Whole body weight, g) ×100

Statistical Analysis

Results were presented as mean ± SD. A one-way ANOVA was used to analyze the data, and the means werecompared using Duncan’s multiple range test. All the analyses were performed using SPSS 21.

Results

Water Quality Parameters

The average temperature recorded in this experiment did not differ significantly among all treatments (Table 1). A significant lower (p < 0.05) dissolved oxygen (DO) level was observed in FRB (5.95 ± 0.40 mg/L) compared to RBB (6.55 ± 0.50 mg/L) and HFRB (6.15 ± 0.10 mg/L). The highest DO and COD levels were recorded in the RBB treatment (Table 1). The average values for biological oxygen demand (BOD), total dissolved solids (TDS), and pH were highest in RBB treatment, while TDS and BOD had the highest average values in FRB treatment. HFRB treatment recorded the highest average value for nitrite. A significantly lower value of pH (6.75) was recorded in HFRB treatment (p < 0.05).

Table 1: Physicochemical parameters of water in a catfish biofloc system where rice bran, fermented rice bran, and hydrolyzed fermented rice bran (HFRB) were used as carbon sources.

Carbon sources
 

Parameters

Rice bran (RBB) Fermented rice bran (FRB) Hydrolyzed fermented rice bran (HFRB)

Significant level

Temp °C

27.80 ± 0.30a

27.50 ± 0.50a 27.60 ± 0.40a

P > 0.05

pH

7.70 ± 0.10a

7.20 ± 0.35b 6.75 ± 0.50c

P < 0.05

TDS (mg/l)

195.00 ± 10.00a

243.00 ± 15.50b 205.00 ± 18.50c

P < 0.05

COD (mg/l)

102.50 ± 5.50a

115.20 ± 8.70b 98.00 ± 5.50b

P < 0.05

BOD (mg/l)

55.50 ± 6.50a

60.45 ± 10.50a 41.50 ± 8.00b

P < 0.05

DO (mg/l)

6.55 ± 0.5a

5.95 ± 0.4ab 6.15 ± 0.10b

P < 0.05

TAN (mg/l)

3.85 ± 0.55a

2.52 ± .0.45b 2.60 ± 0.50b

P < 0.05

Nitrite (mg/l)

0.35± 0.10a

0.30± 0.10b 0.33 ± 0.10c

P < 0.05

Means with a different superscript in the same row are significantly different (P < 0.05).

Floc Production

The biofloc volume was significantly higher in HFRB starting from week 2 of the experiment compared to all other treatments (Figure 1). The floc volume reached maximum in week 7 with values of 135.1 ml/l, 166.6 ml/l, and 111.0 ml/l for HFRB, FRB, and RBB treatments, respectively.

fig 1

Figure 1: Floc production in the catfish biofloc system where rice bran, fermented rice bran, and hydrolyzed fermented rice bran were used as carbon sources.

Growth Parameters and Feed Efficiency

The growth rates, survival, and feed utilization of catfish in the biofloc system for the 8 weeks of rearing (Table 2) showed that treatment of rice bran through solid phase fermentation and acid hydrolysis enhanced its utilization as carbon sources in biofloc as the final weight and specific growth rates were higher compared with untreated rice bran. The highest final weight (85.5 g) was recorded in HFRB treatment, while the lowest value of weight gain (80.26) was in RBB. The feed conversion ratio was also highest in HFRB treatment. The survival was however lowest in HFRB, and this was significant (P < 0.05). The growth of catfish in biofloc utilizing hydrolyzed fermented rice bran as a carbon source in this experiment was better than that in untreated bran, as the growth rates were higher. The best FCR obtained for catfish (1.52 ± 0.05) was recorded in HFRB treatment, and this was significantly higher (P < 0.05). The percentage survival was significantly lower in HFRB treatment (P < 0.05).

Table 2: Growth parameters of catfish reared in a biofloc system where rice bran, fermented rice bran, and hydrolyzed fermented rice bran were used as carbon sources.

Parameters

Rice bran (RBB) Fermented rice bran (FRB)

Hydrolyzed rice bran (HFRB)

Initial weight (g)

11.15 ± 1.60a

11.15 ± 1.60a

11.55 ± 1.60a

Final weight (g)

80.26 ± 3.20a

81.70 ± 2.50b

85.50 ± 2.55b

Absolute growth (g)

70.15 ± 2.80a

70.65 ± 1.80c

74.53 ± 1.50b

Absolute growth rates(g/day)

0.992 ± 0.03a

1.000 ± 0.03c

1.031 ± 0.02b

Relative growth (%)

8.643 ± 0.21a

8.695 ± 0.11a

8.964 ± 0.10b

Specific growth rate(%/day)

1.211 ± 0.16a

1.23 ± 0.14a

1.28 ± 0.13b

Survival%

92 ± 1.55a

95 ± 1.50a

86 ± 1.52b

Feed conversion ratio

1.65 ± 0.04a

1.68 ± 0.03a

1.52 ± 0.05b

Protein efficiency ratio

0.403 ± 0.03a

0.405 ± 0.04a

0.421 ± 0.05b

Means (n=10) followed by different letters in each rows are significantly different (P < 0.05).

Condition Indices

Condition factor (Fulton factor) calculated showed that catfish in the FRB treatment had higher values (0.54) followed by those in RBB (0.47) and HFRB (0.44) treatment fishes (Figure 2). Similar trends were observed with hepatosomatic index and viscerosomatic index in this experiment. The HIS showed a significantly higher value of 5.9% in the FRB treatment (P < 0.05).

fig 2

Figure 2: HIS (hepatosomatic index), CF (condition factor), VSI (viscerosomatic index) African catfish, C. gariepinus fingerlings reared in a biofloc system where rice bran, fermented rice bran, and hydrolyzed fermented rice bran were used as carbon sources.

Discussion

This experiment demonstrated that differential treatment of rice bran influenced its performance as a carbon source in biofloc production of catfish. Even though fermented bran has been well researched in this system, our findings suggest that acid-hydrolyzed fermented rice bran also has potential for consideration as well. Acid hydrolysis of rice bran resulted in the conversion of its starch and cellulose components into reducing sugar [11]. This may improve its performance in carbon release in the biofloc system. Slow carbon release by rice bran has been attributed to its low performance as a biofloc carbon source [5,21]. Rice bran is a cheap carbon source; efforts towards boosting its carbon release have been the focus of research. All the water quality parameters recorded in the system were within the range recommended for aquaculture and catfish production. Temperature is an important ecological factor with a profound effect on fitness, growth, and metabolism performance in aquatic organisms [22-24]. Variations in the temperature in our research were not significant, indicating no external influence on the treatment used. DO is an important abiotic factor influencing the growth and survival of fish. A significant reduction in the level of dissolved oxygen (DO) observed in FRB compared to the rest of the treatment could be due to higher microorganisms in this system, as reported in previous findings [25-27]. The pH range of 7-8.5 was said to be suitable for biofloc system performance, while recommends an average pH of 6.7, as biofloc systems tend to lose their buffering capacity at lower pH. The stability of the bioflocs was found to be dictated by the pH. All the treatments used in the current research maintained the pH of catfish biofloc within the recommended range [28-31], even though the pH level in the HFRB treatment was significantly lower (P < 0.05). Recovery of the acid after the hydrolysis process is a major bottleneck, and this informed our modified method for reducing acid utilization in the hydrolysis process. Future research towards optimizing acid hydrolysis of bran for biofloc carbon usage may be important. The survival rates of RBB and FRB treatments were significantly higher (P < 0.05) than HFRB treatments. This may be connected to lower pH in HFRB treatment. In this study, a higher concentration of total ammonium nitrate was recorded in HFRB treatment even though not significant (P > 0.05). This is in line with the findings of [27,32], who reported the use of complex carbon such as bran to decrease ammonia concentration in biofloc when compared to other carbon sources with simple sugar. The growth parameters of the catfish in the biofloc system after 8 weeks of rearing in this experiment showed that treatment of rice bran through solid phase fermentation and fermentation after acid hydrolysis enhanced its utilization as carbon sources in biofloc as the final weight and specific growth rates were higher compared with untreated rice bran. Organosomatic indices of catfish in this research showed a direct link between the effects of change in carbon source and environment on the fish; the response in such indices in response to nutrition has been well reported [33,34]. The use of acid-hydrolyzed fermented bran in this research proved efficacious in the system, as the growth parameters of this fish therefrom were well above the untreated rice bran treatment. The floc level was also higher in the hydrolyzed fermented bran treatment in this research. The observed drawback in this use of hydrolyzed bran is the low pH produced in the biofloc system. This might account for the reduced survival rates of the fish in this system. In conclusion, the results of this study suggest that hydrolyzed fermented rice bran can be used in catfish biofloc systems as a carbon source without negative consequences on water quality, growth, and feed utilization. However, adjusting the pH may be required for better performance and is recommended. Further research is needed to investigate the optimal hydrolization condition of bran for their usage as carbon sources in biofloc systems.

Acknowledgements

We would like to thank, Umaru Musa Yar’Adua University for their technical assistance. This work was supported by the Tertiary Education Trust Fund, Nigeria.

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Participation of the Leukemia Inhibitory Factor on Ovarian Function

DOI: 10.31038/EDMJ.2024833

Abstract

Leukaemia inhibitory factor (LIF), a cytokine in the interleukin 6 family, is considered a pleiotropic molecule with diverse functions and is expressed in different tissues and cell types. The role of LIF in the reproductive system during the implantation process has been described; however, to date, there is little available information about the effect of LIF on the function and development of the female gonad. The focus of this review is to analyse the structure of LIF, the signalling pathway involved, and the expression of LIF and its receptor in different ovarian cell types. In addition, the participation of LIF and its receptor in ovarian function, follicular development, steroidogenesis and ovulation is discussed.

Introduction

Leukaemia inhibitory factor (LIF) is a cytokine that belongs to the interleukin 6 (IL-6) family and is considered a pleiotropic molecule since it is expressed in different tissues and cell types and has diverse functions. The first observed effect of LIF was its ability to function as a differentiation inducer and proliferation inhibitor of the myeloid leukemic cell line (M1) to macrophages in an in vitro model [18]. Other specific functions of LIF have been reported, such as its participation in bone resorption [36,37] neonatal neuronal transdifferentiation [40,41] and its involvement in cardiac remodelling [19-21], folliculogenesis and spermatogenesis [14]

Currently, the study of this cytokine in the female reproductive system has attracted interest since it is found in different tissues of the female reproductive system [22]. LIF was initially discovered to be necessary for the uterine implantation process [10], and in recent decades, it has been found to be present in the oviduct [23] and ovary, but its functions at these levels have not been fully understood. In the ovaries of different species and from different study models, both in vitro and in vivo, LIF has been shown to fulfil important functions depending on folliculogenesis stage, mainly during the neonatal and fertile periods of female reproductive life; however, the role of LIF during the female subfertile period is unclear. Therefore, in the present review, we discuss the available data on the role of LIF in ovarian folliculogenesis during female reproductive life.

Lif and Its Receptor

LIF is a protein with an approximate molecular weight of 20 kDa, but its molecular weight can range from 38-67 kDa due to differences in posttranslational modifications [38,39]. Among the modifications that mature proteins present are glycosylations, which are mainly associated with asparagine residues. Although glycosylations explain, to some extent, the variations in the molecular weight of LIF (38-67 kDa) [3], we still cannot determine how the glycosylation pattern affects the function and stability of the protein. LIF is described as long-chain cytokine with four α-helices in an up-down-up configuration, as has also been shown for other IL-6 family members such as ciliary neurotrophic factor (CNTF), growth hormone (GH), granulocyte colony-stimulating factor [42,45] Although a low degree of homology is observed between the primary structures of these cytokines, they show a high degree of homology in their tertiary structures and in the functional epitopes of their receptors, as demonstrated by X-ray crystallography resonance imaging [43].

Lif Receptors as a Heterodimer and Associated Signalling Pathways

For LIF to carry out its action, it must interact with a heterodimeric plasmatic membrane receptor formed by two proteins, gp130 and LIFRβ. The LIFRβ subunit which can also interact with other cytokines of the IL-6 family, such as CNTF and oncostatin M and the gp130 is a subunit common for all IL-6 family cytokines [46]. LIF interacts specifically and directly with the LIFRβ subunit but with a relatively low affinity (Kd=1∗10−9). When the gp130 subunit interacts with the LIF-LIFRβ complex, a high-affinity trimeric LIF-LIFRβ-gp130 complex is formed (Kd=1∗10^−10), which is necessary for receptor activation and therefore intracellular signalling [24]. The interaction between LIF and LIFRβ is 80-fold greater than that between LIF and gp130, which is not surprising given that gp130 also interacts with other cytokines [25].

IL-6 family cytokine-associated receptors do not exhibit kinase activity. The binding of LIF to its heteroreceptor causes conformational changes in the subunits that allow cytoplasmic activation of Janus kinase (JAK), tyrosine phosphorylation of the heteroreceptor and phosphorylation of signal transducer and activator of transcription (STAT). It has been observed that LIF can activate the JAK1/STAT3 pathway, which is considered to be the canonical signalling pathway involved (Figure 1), but importantly, the JAK/STAT signalling cascade is a signalling pathway shared by several cytokine receptors [47]. In addition to activating the JAK/STAT pathway, the interaction between LIF and LIFR can activate other signalling pathways, such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways; however, the effects vary and may even be opposite depending on the cell type involved, having been observed to either induce or inhibit cell differentiation in a variety of cases [48].

fig 1

Figure 1: Canonical LIF signaling pathway in the ovarian follicle. LIF is expressed in the ovaries of various animal models, such as mice, rats, nonhuman primates, and humans. Specifically, it has been observed that LIF is expressed in different ovarian cells such as theca cells, granulosa cells and oocyte. In the scheme, granulosa cells of antral follicles are used as an example of localization of the signaling cascade associated with LIF. The LIF molecule is shown in green. The LIF receptor as a heterodimer consists of the LIFRβ subunit in blue and the gp130 subunit in red. Upon interaction of LIF with the LIFRβ subunit of the LIF receptor, the gp130 subunit is recruited to form the heterotrimer. When this occurs the signaling cascade is triggered where JAK1 phosphorylation is induced to be activated. JAK1 upon activation subsequently phosphorylates STAT3 so that it can homodimerize and translocate to the nucleus to act as a transcription factor in the regulation of gene expression.

Role of Lif in the Female Reproductive System

Function of Lif In Utero

It has been widely reported that LIF participates in the implantation process in the uterus of several mammals [50,51]. An increase in LIF levels in utero has been observed at 2 crucial moments of pregnancy: the first is in the oestrus stage, coinciding with the ovulation process [57], and the second is on the 4th and 5th days of pregnancy. In situ hybridization has shown that LIF expression in pregnant mice is confined to the endometrial glands [39]. After the 5th day of pregnancy, once implantation and decidualization occur, the glands begin to degenerate, and LIF secretion ceases. This observation suggests that the peak LIF signal produced during pregnancy could be decisive at the time of implantation; this was corroborated in female LIF-deficient (LIF-/-) homozygous mice whose ova fertilized by either LIF-/- or wild-type (WT) males reached the blastocyst stage without problems. However, these mice could not reach the implantation stage [49] when these embryos were transferred to a pseudopregnant WT female, the pregnancy reached full term, suggesting that the implantation failure was due to a maternal defect, which was essentially attributed to the lack of LIF. Based on these studies, LIF was found to be a fundamental factor in the implantation process. However, the action of LIF in this process is subject to regulation by other factors, including kisspeptin (KP).

KP is a key neuropeptide involved in the regulation of reproductive function through the hypothalamic-pituitary-gonadal (HPG) axis [52]. Despite the important role of the KP at the central level, it also regulates gonadotrophins secretion [26,27]. Calder et al. confirmed that KP (Kiss1-/-) deficient female mice mated with WT males are unable to achieve pregnancy due to implantation defects [11]. This finding led us to consider whether Kiss1-/- females lacked some determinant signals for the implantation process. In this regard, as mentioned above, studies have shown that LIF is an essential factor for the implantation process in mice. Indeed, a therapy based on the exogenous administration of recombinant LIF was able to partially rescue the implantation process in Kiss1-/- females. Based on these findings, it was hypothesized that LIF expression was reduced in female Kiss1-/- mice, which was subsequently confirmed by the marked reduction in LIF expression at the level of the uterine glandular lumen in Kiss1-/- females compared to WT female mice. This is the first study to demonstrate that uterine KP signalling regulates glandular levels of LIF.

Function of Lif in Ovary

LIF is expressed not only in endometrial tissue in the female reproductive system but also in the ovary (Senturk & Arici 1998). LIF is expressed in the ovaries of various animal models, such as mice, rats, nonhuman primates, and humans [5,6,31,32]. During the fertile stage in human and nonhuman primates, LIF has been shown to be present in the follicular fluid of preovulatory follicles [30]. In rats, ovarian LIF levels change during the oestrous cycle, with the highest levels being observed at the night of proestrus, corresponding to oestrus and metaestrus/diestrous [28,29]. We have seen in a rat model that the ovarian expression of LIF, in addition to being different during the oestrous cycle, is different during the reproductive life of the rat, as indicated by a greater expression of this cytokine in the fertile stage and a markedly lower expression during lactation. In neonatal rats, LIF is localized to granulosa cells in primordial and primary follicles and in oocytes [53]. In mouse ovaries, LIF is localized to cumulus cells and oocytes from antral follicles. In these cells, the intensity of the LIF marker increases in growing and mature follicles [54]. According to the IHC technique, LIF is localized in theca cells, granulosa cells and oocytes from healthy antral follicles and mainly in luteal cells of the corpus luteum in fertile rats in the oestrous stage [58]. These data suggest a possible autocrine/paracrine role of LIF during the neonatal and fertile periods in females, as well as a role in the stages of cyclical recruitment, ovulation, corpora lutea development and steroid hormone production.

This paracrine or autocrine action of LIF is suggested by the fact that ovarian cells express LIF receptors. The LIF receptor has been found to localize to different ovarian follicular cells in different species [44]. In the ovaries of fertile female monkeys, LIFRβ and gp130 (also known as IL6ST) are localized by IHQ in theca cells and granulosa cells of antral follicles [33]. In humans, LIFRβ and gp130 have been identified by RT‒qPCR and IHQ in granulosa cells and oocytes from primordial follicles of foetal ovaries and in granulosa cells from primary and secondary follicles in adult ovaries [1]. The activation of the LIF receptor in ovarian follicular cells of monkeys in the fertile stage and in the human granulosa cell line COV434 is related to the signalling pathway corresponding to JAK1/STAT3 (Figure 1) and phosphorylated STAT3 after an ovulatory stimulus [35]. On the other hand, in vitro studies in pig ovaries revealed an increase in the phosphorylated form of STAT3 associated with the cumulus–oocyte complex [34]. We recently reported that, in rat ovaries incubated with LIF for 30 minutes, STAT3 phosphorylation increases [37]. LIF and its receptors can activate other signalling pathways [23] in a paracrine or autocrine manner. It must be determined whether these signalling pathways can also be activated in the ovary, for which further studies are needed.

Participation of LIF in Follicular Recruitment

LIF has been shown to promote the transition from primordial to preantral follicle in a neonatal rat and goat in vitro study [58,59] and it has been proposed that this effect in rats is indirect and mediated by an increase in the expression of kit ligand (KL), a known factor that promotes the passage from primordial to primary follicles. We recently published results that support the idea that chronic treatment with LIF for 28 days in vivo decreases the total number of small primary and secondary follicles in the ovaries of fertile rats. In contrast, the number of primordial follicles does not change with LIF treatment and therefore does not explain the decrease found in primary and secondary follicles. LIF has been shown to decrease the growth of developing follicles both in vitro in prepubertal mice [55] and in vivo in fertile rats [56] Specifically, it has been observed in vitro that both secondary and antral follicles are small in size when ovaries are incubated with LIF [60]. This decrease in the development of preantral follicles disagrees with the results of Nilsson et al. and may be due to the chronic in vivo treatment of LIF. However, the effects of LIF on apoptosis are still controversial [16]. To determine whether LIF induces apoptosis in vivo, it is necessary to carry out studies with shorter treatment durations because at 28 days, no pyknotic nuclei were observed during the morphology analysis. LIF regulates the recruitment of primordial follicles, which is relevant for maintaining the cohort of reserve follicles in the ovary. Its effect could be associated with the maintenance and avoidance of a massive loss of the ovarian follicular reserve during reproductive life. Studies focused on the subfertility stage are also necessary.

Follicular atresia corresponds to the degeneration or death of the ovarian follicle so that healthy follicles can develop normally, while defective follicles degenerate and die by apoptosis or autophagy, depending on the stage of follicular development [12,51]. Autophagic atresia has been documented to occur mainly in preantral follicles, whereas apoptosis-induced atresia occurs mainly at the antral follicle stage during cyclical recruitment. It has been observed that atresia in antral follicles is due to the lack of FSH signalling [53] and that this process is associated with the activation of the LIF-STAT3 pathway in the granulosa cells of bovine ovarian follicles [24]. FSH is important for the selection and development of antral follicles, mainly through cyclical recruitment [66]. However, treatment with LIF in rat ovaries for 28 days does not induce follicular atresia, and serum FSH levels do not change with respect to those of the control at the end of treatment. These results suggest that LIF alone does not have an effect on follicular atresia, and it is probable that atresia due to lack of FSH is due to another mechanism and not through LIF.

Participation of LIF in Ovulation and Corpus Lutea

The effect of LIF on ovulation has been evaluated by Murphy et al., 2016. In this work, LIF concentrations were determined in the follicular fluid of preovulatory follicles of fertile female rhesus macaques, and an increase in LIF was observed after hCG administration as an ovulatory stimulus and prior to ovulation. A similar phenomenon has been observed in follicular fluid from preovulatory follicles in humans after hCG has been administered [13]. These results support the premise that LIF is produced in granulosa cells, cumulus cells, and oocytes, as has been observed in rodents [65]. LIF is produced during all stages of follicular development, apparently regulating the growth and maturation of follicles and oocytes and ultimately contributing to ovulation. In summary, the data suggest that LH can stimulate the production and secretion of LIF in granulosa cells, specifically in preovulatory follicles, which express the LH receptor (LHR), to promote ovulation. For example, the administration of hCG (500 IU/ml) provoked a significant increase in intrauterine LIF, VEGF and MMP-9 (Licht et al., 2007).

There are no data in humans that evaluate the effect of LIF on ovulation itself, but when determining the concentration of LIF in the follicular fluid and in the serum of women suffering from polycystic ovarian syndrome (PCOS), a condition characterized by oligo- or anovulation, women with PCOS have decreased levels of LIF compared to what is observed in control women [64]. A study carried out in a rat model revealed that local LIF administration to the ovary for 28 days can increase the number of large corpora lutea and the serum progesterone concentration at the end of 28 days of treatment with LIF. Large corpora lutea are associated with recent ovulation of preovulatory follicles and increased progesterone production [15]. This is because the luteal cells of newly formed corpora lutea express higher levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) than do those of involuting corpora lutea (from previous ovulations), suggesting that LIF could be important for the ovulatory process. In addition, luteal cells present positive immunoreactivity for LIF in the ovaries of fertile rats, and the highest levels of the messenger RNA that codes for LIF are detected in oestrous and metaestrus/diestrus [63], stages of the oestrous cycle, where the greatest amount of progesterone is produced and newly formed corpora lutea are observed. It is possible that LIF may also influence the survival of the corpora lutea, but this possibility requires further study. LIF not only locally regulates the ovulatory process but also participates at the central nervous system level. LIF induces an increase in GnRH at the hypothalamic level, regulating reproductive function locally in the gonad and in the central nervous system [17].

LIF Involvement in Ovarian Steroidogenesis

However, studies regarding the effect of LIF on steroidogenesis are rare. The first observations of the possible effect of LIF on this process were obtained from experiments carried out in the adrenal cortex and in the human adrenocortical cell line NCI-H295R, where the results indicated that LIF could increase the secretion of cortisol and aldosterone through a mechanism mediated by ACTH [4,8]. On the basis of these findings, LIF can increase the expression of the regulatory protein of acute steroidogenesis (StAR) [62], and in vitro studies of Leydig cells from immature rats incubated with different concentrations of LIF revealed that at low concentrations, this cytokine could increase androgen production, apparently increasing the expression of StAR and 17-hydroxysteroid dehydrogenase 3 (Hsd17b3) [61]. In both cases, LIF can increase the expression of the StAR protein in vitro, which suggests, on the one hand, that the increase in steroid hormone levels in vitro is due to this effect and, on the other hand, that this phenomenon could be replicated in cells of other steroidogenic tissues, such as the ovary. However, until now, there has been no published evidence supporting the involvement of LIF in enzymes or transporters involved in ovarian steroidogenesis.

Conclusions and Perspectives

LIF is a pleiotropic cytokine that has various functions and activates various intracellular signalling pathways, depending on the cell type and tissue in which it participates. The LIF-LIFR system has been studied in the immune system and cancer, and its therapeutic role has been studied in various pathologies; its participation in the implantation process and therapeutic use in the reproductive system have been described. Recently, publications on the role of the male gonad in development and spermatogenesis have emerged. In this review, we analysed the participation of LIF in the ovary and discussed its possible signalling pathways and localization in different cell types in the female gonad. LIF is expressed at different levels during the oestrous cycle stage, and during ovary development, it participates in follicular development, ovulation (Figure 2) and steroidogenesis. We cannot exclude our analysis because, in the context of infertility pathology caused by ovarian dysfunction, LIF could also play a key role in considering future therapy or therapeutic use, but further studies are needed.

fig 2

Figure 2: Summary scheme of the effects of LIF on ovarian folliculogenesis. As discussed in the review, LIF can modulate the different stages of ovarian folliculogenesis in vitro and in vivo. During initial recruitment (passage from primordial follicle to preantal follicle), LIF promotes recruitment by increasing the number of developing follicles (primary and secondary follicles) in an in vitro neonatal ovary model [43]. In the fertile stage, LIF produces a decrease in the number of preantral follicles, in an in vivo model [48]. In studies carried out in the prepubertal stage [27] and in the fertile stage, it is observed that LIF decreases the size and number of antral follicles. It has also been observed that LIF is necessary for ovulation to occur [41], which could be closely related to the increase in the number of large corpora lutea following chronic treatment with this cytokine.

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